0%
BRCA2c.1644G>ALikely benign
Print report
Variant interpretation report

BRCA2 c.1644G>A, p.Gln548=

NM_000059.4:c.1644G>A NP_000050.3:p.(Gln548=) Synonymous · exon 10 View identifiers
Classification
Likely benign

Variant description:

The BRCA2 NM_000059.4:c.1644G>A (NP_000050.3:p.(Gln548=)) synonymous variant has previously been reported in somatic cancers (COSMIC; COSV66452122, n = 1 time). Based on available guidelines, this variant is considered to be Likely Benign. This variant is considered to be Benign by the VCEP (Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA); ClinVar ID 51164).

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BRCA2

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen BRCA2 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BP1Strong
BP1 · strong

Met at strong strength: the variant is silent, lies outside aa 10–40 and 2481–3186, and SpliceAI max delta is 0.003.

BP6Supporting
BP6 · supporting

Not applicable: the ENIGMA BRCA2 VCEP explicitly marks BP6 as Not Applicable.

Recorded classification: Likely benign

Likely Benign: BP1 (strong benign) plus BP6 (supporting benign) satisfy the ENIGMA BRCA2 VCEP's Likely Benign combination.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
81 / 1,614,046 alleles

gnomAD v4.1: 81 / 1,614,046 alleles. Recorded AF 5.01844e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000230111; MAF= 0.02301%, 65/282472 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00325815; MAF= 0.32581%, 65/19950 alleles, homozygotes = 0); grpmax FAF= 0.00269864.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016284876777765715, 3/18422 alleles, homozygotes = 0).

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.003 maximum delta

Recorded SpliceAI maximum delta score: 0.003. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
11 reported laboratory submissions

8 Benign · 3 Likely benign. ClinVar API review status: reviewed by expert panel.

Applied · BP6 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV66452122, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 1 not met · 13 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

All three requested consequence/LOF criteria are not applicable under ENIGMA BRCA2 VCEP v1.2: the variant is a synonymous exon 10 SNV, p.Gln548=, with no protein-length change or null consequence.

The four governing VCEP full-text files were searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant entry was found.

For NM_000059.4:c.1644G>A (p.Gln548=), PP3 is not met because SpliceAI max delta score=0.003 is below the VCEP threshold of 0.2.

BP4 and BP7 are not_applicable because the silent variant is outside the ENIGMA-defined BRCA2 clinically important domains aa 10-40 and aa 2481-3186.

Met · 2

BP1 StrongVCEPMet at strong strength: the variant is silent, lies outside aa 10–40 and 2481–3186, and SpliceAI max delta is 0.003. Details ▾Hide ▴
Reasoning

The ENIGMA BP1 rule applies BP1_Strong to silent substitutions outside a potentially clinically important functional domain when SpliceAI is ≤0.1. The variant is synonymous at residue 548, outside the VCEP-defined BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186. SpliceAI reports max delta score 0.003, meeting the ≤0.1 requirement. Therefore BP1_Strong is met.

VCEP rule
**Apply BP1_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.
Evidence considered
  • The variant is NP_000050.3:p.(Gln548=), a synonymous substitution at residue 548.
  • The ENIGMA-defined BRCA2 clinically important domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 548 is outside both.
  • SpliceAI result for NM_000059.4:c.1644G>A: DS_AG 0.000, DS_AL 0.001, DS_DG 0.003, DS_DL 0.001; max delta score 0.003, which is ≤0.1.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗spliceai ↗
BP6 SupportingVCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly marks BP6 as Not Applicable. Details ▾Hide ▴
Reasoning

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Benign.

VCEP rule
Not Applicable
Evidence considered
  • The ENIGMA BRCA2 CSPEC criterion entry for BP6 has applicability set to Not Applicable.
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 1 · evaluated, threshold not reached

PP3 VCEPNot met: SpliceAI maximum delta score is 0.003, below the ENIGMA PP3 threshold of 0.2 for predicted splicing in silent variants. Details ▾Hide ▴
Reasoning

The variant is a silent substitution, so the applicable PP3 path is predicted splicing rather than protein-impact prediction. The ENIGMA BRCA2 rule requires SpliceAI >=0.2 for silent variants. SpliceAI reports DS_AG 0.000, DS_AL 0.001, DS_DG 0.003, and DS_DL 0.001; the maximum delta score is 0.003, below 0.2. Therefore PP3 is not met. No variant-specific pre-assigned PP3 code was found in SupplementaryTables_V1.2_2024-11-18.xlsx or PMID_22505045_Houdayer_2012_HumMutat.pdf when searched under c.1644G>A, p.Gln548=, and p.Q548=.

VCEP rule
Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • ENIGMA Specifications V1.2, PP3: predicted splicing applies to silent variants when SpliceAI is >=0.2.
  • SpliceAI Lookup for NM_000059.4:c.1644G>A: DS_AG=0.000, DS_AL=0.001, DS_DG=0.003, DS_DL=0.001; max delta score=0.003.
  • SupplementaryTables_V1.2_2024-11-18.xlsx was searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching row was found.
  • PMID_22505045_Houdayer_2012_HumMutat.pdf was searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching entry was found.
Still missing
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗spliceai ↗vcep_supplementarytables_v1_2_2024_11_18 ↗

Not assessed · 13 · no assessment recorded

PS1 VCEPNot assessed: no VCEP-listed pathogenic or likely pathogenic comparator with the same protein or splicing consequence was available. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits PS1 for a predicted missense substitution matching a previously classified pathogenic or likely pathogenic variant, or for an exonic/intronic variant with the same predicted splicing impact as a previously classified (likely) pathogenic variant. This variant is synonymous (NP_000050.3:p.(Gln548=)); the available evidence contains no VCEP-listed pathogenic or likely pathogenic comparator with the same protein or splicing consequence, and no matching comparator was found in the governing VCEP tables. Therefore PS1 cannot be assigned from the available evidence.

VCEP rule
Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply PS1_Variable Weight, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
Evidence considered
  • The case normalization identifies NM_000059.4:c.1644G>A as NP_000050.3:p.(Gln548=), a synonymous variant.
  • The governing ENIGMA specification provides missense and same-splicing-event PS1 routes, but no qualifying pathogenic or likely pathogenic comparator for this variant was available.
Still missing
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PS3 VCEPNot assessed: no variant-specific calibrated functional assay entry or damaging-effect result was found for c.1644G>A (p.Gln548=). Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP rule reserves PS3 for well-established functional studies showing a damaging effect, with protein-only or combined mRNA/protein assays evaluated using calibrated Table 9 recommendations. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, HUMU-40-1557-s001.xlsx, Specifications_V1.2_2024-11-18.docx, and Appendices_V1.2_2024-11-18.docx found no entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548=. The available paper extracts likewise contain no variant-specific functional assay result for this synonymous variant; therefore PS3 cannot be evaluated from the governing evidence and is not_assessed.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.
Evidence considered
  • Specifications_Table9_V1.2_2024-11-18.xlsx, searched by c.1644G>A, p.Gln548=, p.Q548=, and 1644/548 notation: no matching variant row found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, searched by c.1644G>A, p.Gln548=, p.Q548=, and 1644/548 notation: no matching variant row found.
  • HUMU-40-1557-s001.xlsx, searched by c.1644G>A, p.Gln548=, p.Q548=, and 1644/548 notation: no matching variant row found.
  • Specifications_V1.2_2024-11-18.docx, Table 9 description: it provides calibrated published functional-assay code recommendations, but contains no variant-specific result for this variant.
  • Appendices_V1.2_2024-11-18.docx, Appendix E: protein-function PS3/BS3 assignments require consideration of calibrated functional assay results; no variant-specific result for this variant is listed.
  • The available paper extracts for PMIDs 25556971, 25741868, 30702160, 18627636, 23188549, 28392550, and 28726806 explicitly report that c.1644G>A/p.(Q548=) is not mentioned and provide no variant-specific functional result.
Still missing
  • No entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548= found in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548= found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548= found in HUMU-40-1557-s001.xlsx.
  • No variant-specific PS3 functional result for this variant found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific PS3 functional result for this variant found in Appendices_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:25556971 ↗PMID:25741868 ↗PMID:30702160 ↗PMID:18627636 ↗PMID:23188549 ↗PMID:28392550 ↗PMID:28726806 ↗
PS4 VCEPNot assessed: no exact-variant case-control counts, odds ratio, p-value, or confidence interval were found to evaluate the ENIGMA PS4 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA rule requires a case-control study with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. The case literature packet's PS4-indexed papers (PMIDs 23188549, 28392550, and 28726806) were checked through their extracted full-text findings; none mentions BRCA2 c.1644G>A, p.Gln548=, or p.Q548=, and none supplies variant-specific affected-versus-unaffected or population-control counts. The governing ENIGMA supplementary tables, HUMU-40-1557-s001, and Specifications document were searched for c.1644G>A, p.Gln548=, and p.Q548= without an exact variant entry. Therefore the required case-control statistics cannot be evaluated.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.
Evidence considered
  • ENIGMA PS4 rule: affected-individual prevalence must be significantly increased versus controls, with p-value <=0.05, OR >=4, and the lower confidence interval excluding 2.0.
  • PMID:23188549 extracted full-text finding: general hereditary breast/ovarian cancer risk guidance; c.1644G>A and p.(Q548=) were not mentioned.
  • PMID:28392550 extracted full-text finding: 31 BRCA2 variants were detected in a sequencing-method comparison, but c.1644G>A and p.(Q548=) were not reported.
  • PMID:28726806 extracted full-text finding: Canadian laboratory classification comparison; c.1644G>A and p.(Q548=) were not reported.
  • The governing ENIGMA reference files were searched under all requested synonymous-variant notations; no exact row was found, so no OR, p-value, or confidence interval is available.
Still missing
  • SupplementaryTables_V1.2_2024-11-18.xlsx searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact entry found.
  • Specifications_V1.2_2024-11-18.docx searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact entry found.
  • HUMU-40-1557-s001.xlsx searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact entry found.
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx searched for c.1644G>A; no exact BRCA2 row found; this file is not a PS4 case-control source.
  • PMID_31853058_Li_2020_GeneticsInMedicine.pdf searched for the exact variant; no exact variant-level case-control result found.
  • PMID_17924331_Easton_2007_AJHG.pdf searched for the exact variant; no exact variant-level case-control result found.
  • PMID_31853058_methods_supplement.docx searched for the exact variant; no exact variant-level case-control result found.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:23188549 ↗PMID:28392550 ↗PMID:28726806 ↗
PM2 VCEPNot assessed: required non-cancer gnomAD absence and regional depth at least 25 are unavailable, while available all-comers data show the variant is present. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP permits PM2 at Supporting strength only when the variant is absent from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth at least 25. The variant is present in the available all-comers gnomAD v2.1 and gnomAD v4.1 records, but those are not the VCEP-specified non-cancer datasets and cannot establish the required PM2 condition. The required non-cancer observations and read depth are unavailable. No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in the four governing VCEP full-text files.

VCEP rule
Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.
Evidence considered
  • ENIGMA CSPEC PM2 rule: absence from controls in gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer genome datasets, with average regional read depth at least 25.
  • Case gnomAD v2.1 all-comers record shows 65/282472 alleles and AF 0.0002301113, so the variant is not absent from that dataset; it is not the required non-cancer subset.
  • Case gnomAD v4.1 all-comers record shows 81/1614046 alleles and AF 0.0000501844; gnomAD v4.1 is not the VCEP-specified source for PM2.
  • The four governing VCEP full-text files were searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching row was found.
Still missing
  • Required gnomAD v2.1 non-cancer exome absence/allele count is not present in the case evidence.
  • Required gnomAD v3.1 non-cancer genome absence/allele count is not present in the case evidence.
  • Required average regional read depth of at least 25 is not present in the case evidence.
  • No variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM3 VCEPNot assessed: no documented Fanconi Anemia phenotype, qualifying BRCA2 co-occurring pathogenic variant, phase information, or PM3 points are available for c.1644G>A. Details ▾Hide ▴
Reasoning

PM3 requires a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene, with scoring based on phase and the number of unrelated affected individuals. The available case evidence does not document a qualifying Fanconi Anemia phenotype, a pathogenic or likely pathogenic BRCA2 variant in trans or homozygous state, phase-unknown co-occurrence, or PM3 points for this variant. The governing Specifications_V1.2_2024-11-18.docx was searched for c.1644G>A, p.Gln548=, and p.Q548=; no variant-specific entry was found.

VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if: (i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. (ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. See Appendix H Co-occurrent P or LP variant should be assigned classification using VCEP specifications. Variant under assessment must be sufficiently rare (not meeting a benign population evidence code). See Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.
Evidence considered
  • CSPEC PM3 entry: the criterion requires a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene.
  • Specifications Table 6: PM3 points require a BRCA2-related Fanconi Anemia patient with a P or LP variant in trans or homozygote, or phase unknown, and final assignment is PM3_Strong at 4 or more points, PM3 at 2 points, or PM3_Supporting at 1 point.
  • The case evidence bundle contains no documented qualifying Fanconi Anemia presentation, same-gene P/LP co-occurrence, phase determination, or PM3 point assignment for NM_000059.4:c.1644G>A / NP_000050.3:p.(Gln548=).
  • Search of /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA2/fulltext/Specifications_V1.2_2024-11-18.docx.txt for c.1644G>A, p.Gln548=, and p.Q548= returned no match.
Still missing
  • No variant-specific entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_V1.2_2024-11-18.docx; qualifying proband phenotype, same-gene pathogenic-variant co-occurrence, phase, and point-count data remain undocumented.
Sources
cspec ↗
PP1 VCEPNot assessed: no quantitative co-segregation likelihood ratio or affected-family genotype data is available to compare with the PP1 threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires co-segregation in multiple affected family members measured by a quantitative co-segregation method and assigns PP1 strength from the Bayes-score likelihood ratio. The available case evidence contains no proband-level pedigree, parental testing, affected-relative genotypes, meioses, or quantitative co-segregation LR for this variant. The searched on-record reference files also contain no matching c.1644G>A, p.Gln548=, or p.Q548= segregation entry, so PP1 cannot be assigned.

VCEP rule
Co-segregation with disease in multiple affected family members ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1 ... PP1_Moderate – LR≥4.3:1 ... PP1_Strong – LR≥18.7:1 ... PP1_Very Strong – LR≥350:1
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2 PP1 rule requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method and assigns weight by Bayes Score: PP1 LR ≥2.08:1, PP1_Moderate LR ≥4.3:1, PP1_Strong LR ≥18.7:1, and PP1_Very Strong LR ≥350:1.
  • The case evidence provides no quantitative co-segregation LR, pedigree, affected-relative genotype results, parental testing, or meioses for NM_000059.4:c.1644G>A.
  • No exact variant row was found in the on-record SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx files.
Still missing
  • No proband-level pedigree, affected-relative genotypes, parental testing, meioses, or quantitative co-segregation likelihood ratio was available.
  • No matching c.1644G>A, p.Gln548=, or p.Q548= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
PP4 VCEPNot assessed: the exact variant has no available ENIGMA multifactorial clinical likelihood ratio for comparison with the PP4 LR thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits PP4 only for combined multifactorial clinical likelihood data. The exact BRCA2 c.1644G>A entry was not found in the governing clinical-history LR table, and the associated Li, Easton, and methods files contain no exact variant-level result that supplies an LR. Thus no PP4 threshold comparison can be made.

VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1 ... See Specifications Table7 and Appendix B for details.
Evidence considered
  • ENIGMA PP4 rule: breast cancer is common and genetically heterogeneous; PP4 is used only for combined LR towards pathogenicity from multifactorial likelihood clinical data, with supporting LR >=2.08:1, moderate LR >=4.3:1, strong LR >=18.7:1, and very strong LR >=350:1.
  • The exact variant row was absent from the Li et al. BRCA2 clinical-history LR table, so no clinical-history LR is available for a numeric comparison.
Still missing
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx searched for exact Gene=BRCA2 and HGVS c.1644G>A; no row found.
  • PMID_31853058_Li_2020_GeneticsInMedicine.pdf searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant-level LR found.
  • PMID_17924331_Easton_2007_AJHG.pdf searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant-level LR found.
  • PMID_31853058_methods_supplement.docx searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant-level LR found.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗vcep_pmid_31853058_li_2020_geneticsinmedicine ↗vcep_pmid_17924331_easton_2007_ajhg ↗vcep_pmid_31853058_methods_supplement ↗PMID:31853058 ↗PMID:17924331 ↗
BA1 VCEPNot assessed: required non-cancer gnomAD FAF and regional read-depth data are unavailable, so the VCEP's BA1 threshold cannot be applied. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires BA1 to use the maximum filter allele frequency from gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, assessed separately, with read depth at least 20. The available case data provide all-comers gnomAD v2.1 and gnomAD v4.1 frequencies, but do not provide the required gnomAD v2.1 non-cancer exome or gnomAD v3.1 non-cancer genome FAF and do not document the required regional read depth. Therefore BA1 cannot be evaluated under the governing VCEP rule. No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

VCEP rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • ENIGMA CSPEC BA1 rule: maximum filter allele frequency above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with separate exome/genome assessment and no application when read depth is below 20.
  • Case gnomAD v2.1 all-comers record: total AF 0.0002301113, grpmax FAF 0.00269864, East Asian AF 0.0032581454, homozygotes 0; this is not the required non-cancer dataset.
  • Case gnomAD v4.1 all-comers record: total AF 0.0000501844, grpmax FAF 0.0013869, East Asian AF 0.0016936311, homozygotes 0; gnomAD v4.1 is not the VCEP-specified replacement for the required v2.1/v3.1 non-cancer sources.
  • The four governing VCEP full-text files were searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching row was found.
Still missing
  • Required gnomAD v2.1 non-cancer exome FAF for c.1644G>A is not present in the case evidence.
  • Required gnomAD v3.1 non-cancer genome FAF for c.1644G>A is not present in the case evidence.
  • Regional read depth needed for the VCEP BA1 quality-control condition is not present in the case evidence.
  • No variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot assessed: required non-cancer gnomAD FAF is unavailable, so neither VCEP BS1 frequency interval can be applied. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires BS1 to use the maximum filter allele frequency from gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, assessed separately. The case contains only all-comers gnomAD v2.1 and gnomAD v4.1 frequencies, so the required non-cancer FAF cannot be evaluated against either the >0.0001 strong threshold or the >0.00002 to <=0.0001 supporting interval. No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in the four governing VCEP full-text files.

VCEP rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details. ... Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
  • ENIGMA CSPEC BS1 rules: strong above 0.0001 and supporting above 0.00002 through 0.0001, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes with separate exome/genome assessment.
  • Case gnomAD v2.1 all-comers record reports grpmax FAF 0.00269864, but it is not the specified non-cancer source.
  • Case gnomAD v4.1 all-comers record reports grpmax FAF 0.0013869, but gnomAD v4.1 is not the VCEP-specified source for this criterion.
  • The four governing VCEP full-text files were searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching row was found.
Still missing
  • Required gnomAD v2.1 non-cancer exome FAF is not present in the case evidence.
  • Required gnomAD v3.1 non-cancer genome FAF is not present in the case evidence.
  • No variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 VCEPNot assessed: no qualifying phenotyped healthy-adult observation is available, and the VCEP excludes gnomAD frequency observations from BS2 scoring. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP applies BS2 to phenotyped healthy-adult observations in the context of absence of Fanconi Anemia features and assigns points per proband using Table 8. The case documents zero gnomAD v2.1 and zero gnomAD v4.1 homozygotes, but the VCEP explicitly excludes frequency-based gnomAD observations from BS2 point assignment; no phenotyped healthy-adult heterozygote, homozygote, or hemizygote observation is available. Therefore BS2 cannot be assessed.

VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
Evidence considered
  • ENIGMA CSPEC BS2 rule: apply in the absence of Fanconi Anemia features and use Table 8 to assign points per proband and the final BS2 code.
  • The VCEP Appendix H stipulates that BS2 applies only to phenotyped individuals from clinical or research cohorts and is not applied to data used for frequency-based codes; gnomAD observations of at least two homozygotes are captured by BA1 or BS1 instead.
  • Case gnomAD v2.1 reports total homozygotes 0 and case gnomAD v4.1 reports total homozygotes 0; these are frequency observations and do not establish a qualifying BS2 proband.
Still missing
  • No qualifying phenotyped healthy-adult observation with the variant is present.
  • No Fanconi Anemia feature assessment or Table 8 point assignment is present.
  • No variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 VCEPNot assessed: no variant-specific calibrated functional assay entry or no-damaging-effect result was found for c.1644G>A (p.Gln548=). Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP rule reserves BS3 for well-established functional studies showing no damaging effect on protein function, with protein-only or combined mRNA/protein assays evaluated using calibrated Table 9 recommendations. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, HUMU-40-1557-s001.xlsx, Specifications_V1.2_2024-11-18.docx, and Appendices_V1.2_2024-11-18.docx found no entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548=. The available paper extracts likewise contain no variant-specific functional assay result for this synonymous variant; therefore BS3 cannot be evaluated from the governing evidence and is not_assessed.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.
Evidence considered
  • Specifications_Table9_V1.2_2024-11-18.xlsx, searched by c.1644G>A, p.Gln548=, p.Q548=, and 1644/548 notation: no matching variant row found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx, searched by c.1644G>A, p.Gln548=, p.Q548=, and 1644/548 notation: no matching variant row found.
  • HUMU-40-1557-s001.xlsx, searched by c.1644G>A, p.Gln548=, p.Q548=, and 1644/548 notation: no matching variant row found.
  • Specifications_V1.2_2024-11-18.docx, Table 9 description: it provides calibrated published functional-assay code recommendations, but contains no variant-specific result for this variant.
  • Appendices_V1.2_2024-11-18.docx, Appendix E: protein-function PS3/BS3 assignments require consideration of calibrated functional assay results; no variant-specific result for this variant is listed.
  • The available paper extracts for PMIDs 25556971, 25741868, 30702160, 18627636, 23188549, 28392550, and 28726806 explicitly report that c.1644G>A/p.(Q548=) is not mentioned and provide no variant-specific functional result.
Still missing
  • No entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548= found in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548= found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for NM_000059.4:c.1644G>A, p.Gln548=, or p.Q548= found in HUMU-40-1557-s001.xlsx.
  • No variant-specific BS3 functional result for this variant found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific BS3 functional result for this variant found in Appendices_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:25556971 ↗PMID:25741868 ↗PMID:30702160 ↗PMID:18627636 ↗PMID:23188549 ↗PMID:28392550 ↗PMID:28726806 ↗
BS4 VCEPNot assessed: no quantitative non-segregation likelihood ratio or affected-family genotype data is available to compare with the BS4 threshold of LR ≤0.48:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires lack of segregation in affected family members measured by a quantitative co-segregation method and assigns BS4 strength from the Bayes-score likelihood ratio. The available case evidence contains no non-segregating affected relatives, pedigree, parental testing, meioses, or quantitative co-segregation LR for this variant. The searched on-record reference files also contain no matching c.1644G>A, p.Gln548=, or p.Q548= segregation entry, so BS4 cannot be assigned.

VCEP rule
Lack of segregation in affected members of a family. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48 to >0.23:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_Very strong – LR ≤0.00285:1
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2 BS4 rule requires lack of segregation in affected family members measured by a quantitative co-segregation method and assigns weight by Bayes Score: BS4_Supporting LR ≤0.48 to >0.23:1, BS4_Moderate LR ≤0.23:1, BS4 LR ≤0.05:1, and BS4_Very strong LR ≤0.00285:1.
  • The case evidence provides no quantitative non-segregation LR, pedigree, affected-relative genotype results, parental testing, or meioses for NM_000059.4:c.1644G>A.
  • No exact variant row was found in the on-record SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx files.
Still missing
  • No proband-level pedigree, affected-relative genotypes, parental testing, meioses, or quantitative non-segregation likelihood ratio was available.
  • No matching c.1644G>A, p.Gln548=, or p.Q548= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
BP5 VCEPNot assessed: no exact-variant multifactorial LR is available to test against the ENIGMA BP5 <=0.48 supporting threshold. Details ▾Hide ▴
Reasoning

The ENIGMA rule uses combined multifactorial likelihood data against pathogenicity and requires the LR to be at or below the criterion-specific threshold. The exact BRCA2 c.1644G>A row was not found in the governing Li clinical-history LR table, and no exact variant-level LR was found in the associated Li, Easton, or methods files. Therefore the required inequality cannot be evaluated; no BP5 strength is assigned.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5 - LR ≤0.48:1 ... Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.
Evidence considered
  • ENIGMA BP5 supporting rule uses combined LR against pathogenicity from multifactorial likelihood clinical data and requires BP5 LR <=0.48:1; moderate requires LR <=0.23:1, strong requires LR <=0.05:1, and very strong requires LR <=0.00285:1.
  • The exact variant was absent from the governing Li clinical-history LR table, so the required inequality cannot be written with an observed LR: no value <=0.48 can be tested.
Still missing
  • PMID_31853058_BRCA2_clinical_history_LR.xlsx searched for exact Gene=BRCA2 and HGVS c.1644G>A; no row found.
  • PMID_31853058_Li_2020_GeneticsInMedicine.pdf searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant-level LR found.
  • PMID_17924331_Easton_2007_AJHG.pdf searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant-level LR found.
  • PMID_31853058_methods_supplement.docx searched for c.1644G>A, p.Gln548=, and p.Q548=; no exact variant-level LR found.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗vcep_pmid_31853058_li_2020_geneticsinmedicine ↗vcep_pmid_17924331_easton_2007_ajhg ↗vcep_pmid_31853058_methods_supplement ↗PMID:31853058 ↗PMID:17924331 ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: the exon 10 c.1644G>A synonymous SNV preserves p.Gln548 and is not among the VCEP-defined null variant types eligible for PVS1. Details ▾Hide ▴
Reasoning

Not applicable. NM_000059.4:c.1644G>A is a synonymous SNV in exon 10, producing NP_000050.3:p.(Gln548=), not a null variant, protein-termination variant, frameshift, canonical splice-site variant, initiation-codon variant, or exon deletion. The VCEP PVS1 rule is restricted to null variants and directs use of its flowchart for those variant types; the VCEP's Table 4 likewise covers initiation, nonsense/frameshift, deletion, duplication, and canonical donor/acceptor ±1,2 variants, not synonymous substitutions. No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4_V1.2_2024-11-18.xlsx, or PMID_22505045_Houdayer_2012_HumMutat.pdf.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains.
Evidence considered
  • Case consequence facts: NM_000059.4:c.1644G>A; NP_000050.3:p.(Gln548=); synonymous SNV; exon 10; canonical_splice_consensus=false.
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PVS1 row: 'Null variant in a gene where loss of function is a known mechanism of disease.'
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PVS1 row: 'Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains.'
  • ENIGMA BRCA2 Specifications Table 4: PVS1 decision table is organized for initiation, nonsense/frameshift, deletion, duplication, and splice-site donor/acceptor ±1,2 variants; no row matches this synonymous SNV.
Still missing
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗cspec ↗
PS2 VCEPNot applicable: the VCEP explicitly says "Do not use" because de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

PS2 is not applicable under the ENIGMA BRCA2 VCEP specification. The governing entry states: "De novo (paternity confirmed) in a patient with the disease and no family history." It then states "Do not use" because "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences."

VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2 PS2 entry: de novo occurrence with confirmed paternity is followed by "Do not use" and the stated lack of calibration for BRCA1/2-related cancers.
  • The three on-record variant searches found no matching c.1644G>A, p.Gln548=, or p.Q548= entry: SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx.
Still missing
  • No variant-specific entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx; this does not alter PS2 because the VCEP marks it Do not use.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PM1 VCEPNot applicable: ENIGMA says PM1 is not used for BRCA2 and considers it part of PP3/BP4. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly says PM1 is not to be used and that this evidence is considered as part of the bioinformatic analysis under PP3/BP4. The residue is also outside the VCEP-defined BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186); vcep_materials.json contains no gene-specific domain_tables entry.

VCEP rule
Located in a mutational hot spot and/or critical and well-established functional domain. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • The ENIGMA specification marks PM1 'Do not use' and states it is considered as a component of PP3/BP4.
  • The VCEP-defined BRCA2 functional domains are PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 548 lies outside both.
  • vcep_materials.json has no domain_tables entry for BRCA2.
Still missing
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM4 VCEPNot applicable: p.Gln548= causes no protein-length change, while the VCEP limits PM4 to in-frame indels or stop-loss variants and says not to use it. Details ▾Hide ▴
Reasoning

Not applicable. The variant is synonymous and causes no protein length change: NP_000050.3:p.(Gln548=). The VCEP explicitly says PM4 is not to be used and defines it only for protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Neither an in-frame length change nor a stop-loss is present.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use
Evidence considered
  • Case consequence facts: NM_000059.4:c.1644G>A is synonymous and encodes NP_000050.3:p.(Gln548=).
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PM4 row: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.'
  • ENIGMA BRCA2 Specifications v1.2, Table 1, PM4 row: 'Do not use'.
Still missing
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
PM5 N/ANot applicable: the variant is synonymous, while ENIGMA PM5 is not used for missense changes and is repurposed only for PTC variants. Details ▾Hide ▴
Reasoning

The ENIGMA specification marks the missense PM5 route as not to be used and repurposes PM5 only for protein termination codon variants in an exon with a different proven pathogenic PTC. This variant is synonymous, not a missense or PTC variant, so PM5 is not applicable.

VCEP rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4). ... Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1.
Evidence considered
  • The variant is NP_000050.3:p.(Gln548=), a synonymous substitution.
  • The ENIGMA specification states that the missense PM5 route is not used and defines the repurposed PM5 route for protein termination codon variants.
Still missing
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the VCEP explicitly says "Do not use" because de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

PM6 is not applicable under the ENIGMA BRCA2 VCEP specification. The governing entry states: "Confirmed de novo without confirmation of paternity and maternity." It then states "Do not use" because "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences."

VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2 PM6 entry: confirmed de novo without paternity and maternity confirmation is followed by "Do not use" and the stated lack of calibration for BRCA1/2-related cancers.
  • The three on-record variant searches found no matching c.1644G>A, p.Gln548=, or p.Q548= entry: SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and HUMU-40-1557-s001.xlsx.
Still missing
  • No variant-specific entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx; this does not alter PM6 because the VCEP marks it Do not use.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PP2 VCEPNot applicable: ENIGMA says PP2 is not used because BRCA2 has a high frequency of benign missense variants. Details ▾Hide ▴
Reasoning

The ENIGMA specification states that PP2 is not to be used because BRCA2 has a high frequency of benign missense variants. The current variant is synonymous rather than missense in any event, so the PP2 criterion does not apply.

VCEP rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. ... Do not use ... High frequency of benign missense variants.
Evidence considered
  • The ENIGMA specification marks PP2 'Do not use' and gives the reason as 'High frequency of benign missense variants.'
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PP5 VCEPNot applicable: the ENIGMA BRCA2 VCEP explicitly marks PP5 as Not Applicable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP CSPEC entry explicitly marks PP5 as Not Applicable. No PP5 evidence is assigned.

VCEP rule
Not Applicable
Evidence considered
  • The ENIGMA BRCA2 CSPEC criterion entry for PP5 has applicability set to Not Applicable.
Sources
cspec ↗
BP2 VCEPNot applicable: the BRCA2 VCEP says BP2 should not be used except in the context of BS2. Details ▾Hide ▴
Reasoning

The BRCA2 VCEP specification states that BP2 is not to be used and is applied only in the context of BS2. Therefore BP2 is not applicable as an independent criterion for this assessment.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern Do not use Applied only in the context of BS2.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, BP2 row: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern; the row states Do not use and Applied only in the context of BS2.
Sources
cspec ↗
BP3 VCEPNot applicable: this synonymous SNV is not an in-frame deletion or insertion in a repetitive region, and the VCEP explicitly says BP3 is not used. Details ▾Hide ▴
Reasoning

Not applicable. The variant is synonymous, not an in-frame deletion or insertion, and no repeat-region protein-length change is present. The VCEP explicitly marks BP3 'Do not use' and states that the criterion concerns in-frame deletions/insertions in a repetitive region without a known function.

VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use
Evidence considered
  • Case consequence facts: NM_000059.4:c.1644G>A is a synonymous SNV encoding p.(Gln548=), with no in-frame insertion or deletion.
  • ENIGMA BRCA2 Specifications v1.2, Table 1, BP3 row: 'In-frame deletions/insertions in a repetitive region without a known function'.
  • ENIGMA BRCA2 Specifications v1.2, Table 1, BP3 row: 'Do not use'.
Still missing
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.1644G>A, p.Gln548=, or p.Q548= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
BP4 N/ANot applicable: p.Gln548= is outside ENIGMA's defined BRCA2 domains at aa 10-40 and aa 2481-3186, so BP4's silent-variant path does not apply. Details ▾Hide ▴
Reasoning

The variant is silent but lies at amino acid 548, outside the only ENIGMA-defined clinically important BRCA2 domains (PALB2 binding aa 10-40 and DNA binding aa 2481-3186). The BP4 silent-variant path is restricted to a silent variant inside such a domain. This criterion is therefore not_applicable before assessing the SpliceAI result; the available maximum delta score of 0.003 is reported but does not change scope.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.
Evidence considered
  • ENIGMA Specifications V1.2, BP4: the silent-variant path applies only to a silent variant inside a potentially clinically important functional domain, with SpliceAI <=0.1.
  • ENIGMA BRCA2 domain definition: PALB2 binding domain aa 10-40 and DNA binding aa 2481-3186; p.Gln548= is outside both domains.
  • SpliceAI reports max delta score=0.003 for NM_000059.4:c.1644G>A, but this score is not needed to determine BP4 scope.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: BP7 requires a silent variant inside an ENIGMA-defined functional domain with BP4 met, but p.Gln548= lies outside those domains. Details ▾Hide ▴
Reasoning

The variant is silent but is outside the ENIGMA-defined BRCA2 clinically important functional domains. ENIGMA's BP7 silent-variant path applies only to a silent variant inside such a domain and requires BP4 to be met. Because the variant is outside those domains and BP4 is not applicable, BP7 is not_applicable; the SpliceAI maximum delta score of 0.003 does not bring the variant into BP7 scope.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.
Evidence considered
  • ENIGMA Specifications V1.2, BP7: the silent-variant path applies inside a potentially clinically important functional domain only if BP4 is met.
  • ENIGMA BRCA2 domain definition: PALB2 binding domain aa 10-40 and DNA binding aa 2481-3186; p.Gln548= is outside both domains.
Sources
cspec ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.1644G>A
Protein (HGVS p.)
NP_000050.3:p.(Gln548=)
GRCh38
chr13:32333122 G>A
GRCh37
chr13:32907259 G>A
Location and type
Exon 10 · synonymous
ClinVar
51164
COSMIC
COSV66452122

Gene diagram

Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.

BRCA2NM_000059.4
Fetching transcript structure from UCSC…
gnomAD v4.1 81 / 1,614,046 alleles AF 5.02e-05 · 0 homozygotes · FAF 0.00139
gnomAD v2.1 65 / 282,472 alleles AF 0.00023 · 0 homozygotes · FAF 0.0027
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5e-05 · 81 / 1,614,046 alleles · 0 hom · FAF 0.0014
East Asian76 / 44,874 0.0017
Remaining individuals4 / 62,496 6.4e-05
European (non-Finnish)1 / 1,179,994 8.5e-07
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0.00023 · 65 / 282,472 alleles · 0 hom · FAF 0.0027
East Asian65 / 19,950 0.0033
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.01844e-05; MAF= 0.00502%, 81/1614046 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00169363; MAF= 0.16936%, 76/44874 alleles, homozygotes = 0); grpmax FAF= 0.0013869.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000230111; MAF= 0.02301%, 65/282472 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00325815; MAF= 0.32581%, 65/19950 alleles, homozygotes = 0); grpmax FAF= 0.00269864.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016284876777765715, 3/18422 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -87 bp
0.001
SpliceAI acceptor gainat +209 bp
0.000
SpliceAI donor lossat +265 bp
0.001
SpliceAI donor gainat +88 bp
0.003
Pangolin splice lossmagnitude shown
-0.032
Pangolin splice gain
0.002

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta score is 0.003, below the ENIGMA PP3 threshold of 0.2 for predicted splicing in silent variants. Details ▾Hide ▴
Reasoning

The variant is a silent substitution, so the applicable PP3 path is predicted splicing rather than protein-impact prediction. The ENIGMA BRCA2 rule requires SpliceAI >=0.2 for silent variants. SpliceAI reports DS_AG 0.000, DS_AL 0.001, DS_DG 0.003, and DS_DL 0.001; the maximum delta score is 0.003, below 0.2. Therefore PP3 is not met. No variant-specific pre-assigned PP3 code was found in SupplementaryTables_V1.2_2024-11-18.xlsx or PMID_22505045_Houdayer_2012_HumMutat.pdf when searched under c.1644G>A, p.Gln548=, and p.Q548=.

VCEP rule
Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
  • ENIGMA Specifications V1.2, PP3: predicted splicing applies to silent variants when SpliceAI is >=0.2.
  • SpliceAI Lookup for NM_000059.4:c.1644G>A: DS_AG=0.000, DS_AL=0.001, DS_DG=0.003, DS_DL=0.001; max delta score=0.003.
  • SupplementaryTables_V1.2_2024-11-18.xlsx was searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching row was found.
  • PMID_22505045_Houdayer_2012_HumMutat.pdf was searched for c.1644G>A, p.Gln548=, and p.Q548=; no matching entry was found.
Still missing
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.1644G>A, p.Gln548=, or p.Q548= was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗spliceai ↗vcep_supplementarytables_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: p.Gln548= is outside ENIGMA's defined BRCA2 domains at aa 10-40 and aa 2481-3186, so BP4's silent-variant path does not apply. Details ▾Hide ▴
Reasoning

The variant is silent but lies at amino acid 548, outside the only ENIGMA-defined clinically important BRCA2 domains (PALB2 binding aa 10-40 and DNA binding aa 2481-3186). The BP4 silent-variant path is restricted to a silent variant inside such a domain. This criterion is therefore not_applicable before assessing the SpliceAI result; the available maximum delta score of 0.003 is reported but does not change scope.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.
Evidence considered
  • ENIGMA Specifications V1.2, BP4: the silent-variant path applies only to a silent variant inside a potentially clinically important functional domain, with SpliceAI <=0.1.
  • ENIGMA BRCA2 domain definition: PALB2 binding domain aa 10-40 and DNA binding aa 2481-3186; p.Gln548= is outside both domains.
  • SpliceAI reports max delta score=0.003 for NM_000059.4:c.1644G>A, but this score is not needed to determine BP4 scope.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: BP7 requires a silent variant inside an ENIGMA-defined functional domain with BP4 met, but p.Gln548= lies outside those domains. Details ▾Hide ▴
Reasoning

The variant is silent but is outside the ENIGMA-defined BRCA2 clinically important functional domains. ENIGMA's BP7 silent-variant path applies only to a silent variant inside such a domain and requires BP4 to be met. Because the variant is outside those domains and BP4 is not applicable, BP7 is not_applicable; the SpliceAI maximum delta score of 0.003 does not bring the variant into BP7 scope.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.
Evidence considered
  • ENIGMA Specifications V1.2, BP7: the silent-variant path applies inside a potentially clinically important functional domain only if BP4 is met.
  • ENIGMA BRCA2 domain definition: PALB2 binding domain aa 10-40 and DNA binding aa 2481-3186; p.Gln548= is outside both domains.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • BRCA1 and BRCA2 mutations in women from Shanghai China.
    Suter NM et al. · 2004
    No paper-specific finding is recorded.
    PMID 14973102 ↗
  • Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer.
    Trujillano D et al. · 2015
    This paper describes a targeted BRCA1/2 sequencing assay and does not explicitly mention BRCA2 c.1644G>A or provide a variant-specific functional result.
    Does not name this variant
    PMID 25556971 ↗
    Quoted passage
    In the validation cohort, we identified all previously known mutations and variants, including single nucleotide variants and insertions and deletions, achieving a sensitivity of 100%

    Results, Detection of BRCA1 and BRCA2 Variants in the Validation Cohort; Table 2

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    This paper provides general ACMG/AMP guidance and does not report BRCA2-specific data or a functional assay result for c.1644G>A.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.

    Proposed Criteria for Interpretation of Sequence Variants, paragraph 1

  • Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.
    Bhaskaran SP et al. · 2019
    This paper compiles BRCA variation data from Chinese populations and does not explicitly mention BRCA2 c.1644G>A or provide variant-specific functional data.
    Does not name this variant
    PMID 30702160 ↗
    Quoted passage
    By using the rich Chinese BRCA variation data as a representative of non‐Caucasian populations, our study provides solid evidence to conclude the presence of ethnic‐specific BRCA mutation.

    Discussion, first paragraph

  • Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer.
    Thirthagiri E et al. · 2008
    This paper reports BRCA1/2 sequencing and MLPA in Malaysian patients but does not explicitly mention BRCA2 c.1644G>A or provide variant-specific functional data.
    Does not name this variant
    PMID 18627636 ↗
    Quoted passage
    In addition, we identified 47 sequence variants of unknown clinical significance (16 in BRCA1 and 31 in BRCA2), of which eight were found to occur in more than one unrelated family (Table 3). Of these, 26 sequence variants were novel (nine in BRCA1 and 17 in BRCA2).

    Results, Mutation testing outcome; Table 3

  • NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
    This paper does not explicitly mention BRCA2 c.1644G>A or NP_000050.3:p.(Q548=); it provides only general BRCA1/2 disease biology and cancer-risk background.
    Does not name this variant
    PMID 23188549 ↗
    Quoted passage
    BRCA1 and BRCA2 are tumor suppressor genes. Their protein products are involved in the cellular response to DNA damage and double-stranded DNA repair.

    Clinical Features

  • Comparison of Ion Personal Genome Machine Platforms for the Detection of Variants in BRCA1 and BRCA2.
    Hwang SM et al. · 2018
    This paper evaluated BRCA1/2 variant detection using sequencing platforms and does not explicitly report BRCA2 c.1644G>A or provide a variant-specific functional result.
    Does not name this variant
    PMID 28392550 ↗
    Quoted passage
    In BRCA2, 31 variants were identified with 30 exonic variants and one intronic variant. There were seven frameshift variants, 13 missense and 10 synonymous variants.

    Results, Detection of variants

  • Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR).
    Lebo MS et al. · 2018
    This paper compares BRCA1/2 laboratory classifications in a Canadian repository and does not report the specific BRCA2 c.1644G>A variant or a variant-specific functional result.
    Does not name this variant
    PMID 28726806 ↗
    Quoted passage
    A total of 5,554 BRCA1 and BRCA2 variant classifications were submitted between October and November of 2015 by the 11 participating laboratories from Ontario, British Columbia, Alberta, and Manitoba. ... There were 3,014 independent variants among the 5,554 submissions: 1,866 were classified by only one laboratory, 900 were classified by two or more laboratories, and 248 had no classifications ... The 900 variants classified by two or more laboratories had, on average, 3.5 observations. Among these variants, 550 (61.1%) had concordant interpretations and 350 (38.9%) were discordant based on the five-tier comparison model.

    Results, ‘Variants submitted’

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 81 / 1,614,046 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.003 Open source ↗
ClinVar 8 Benign · 3 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.01844e-05; MAF= 0.00502%, 81/1614046 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00169363; MAF= 0.16936%, 76/44874 alleles, homozygotes = 0); grpmax FAF= 0.0013869.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000230111; MAF= 0.02301%, 65/282472 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00325815; MAF= 0.32581%, 65/19950 alleles, homozygotes = 0); grpmax FAF= 0.00269864.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016284876777765715, 3/18422 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 51164)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66452122, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.