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BRCA1c.4683C>GUncertain significance
Print report
Variant interpretation report

BRCA1 c.4683C>G, p.Thr1561=

NM_007294.4:c.4683C>G NP_009225.1:p.(Thr1561=) Synonymous · exon 15 View identifiers
Classification
Uncertain significance

Variant description:

The BRCA1 NM_007294.4:c.4683C>G (NP_009225.1:p.(Thr1561=)) synonymous variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About BRCA1

BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.

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 BRCA1 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: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Strong
BP1 · strong

Met at Strong: silent variant outside all VCEP-defined domains with SpliceAI max delta 0.015, below the required ≤0.1 no-splicing threshold.

Recorded classification: Uncertain significance

VUS: BP1 Strong is the only met criterion; ENIGMA Table 3 requires multiple benign evidence types for Likely Benign from one Strong benign criterion.

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
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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

Recorded SpliceAI maximum delta score: 0.015. Refer to the recorded PP3/BP4 rationale for interpretation.

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

2 Likely benign · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only 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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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 BRCA1 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 3 not met · 12 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

For the requested codon, residue, and domain criteria, BP1_Strong is met; PS1 is not assessed because no qualifying same-splicing pathogenic comparator is available; PM1, PM5, and PP2 are not applicable under the ENIGMA VCEP rules.

PS2 and PM6 are not applicable because the ENIGMA BRCA1 VCEP does not permit calibrated de novo evidence for BRCA1/2-related cancers.

PP1 and BS4 are not assessed because no quantitative segregation or non-segregation likelihood ratio is documented for this variant.

PS4, PP4, and BP5 are not assessed because the required matched case-control or calibrated multifactorial clinical likelihood evidence is unavailable.

PP5 and BP6 are not applicable because the ENIGMA BRCA1 VCEP explicitly says not to use them.

The variant is synonymous at BRCA1 p.Thr1561= and lies outside the ENIGMA-defined RING, coiled-coil, and BRCT functional domains.

The only available computational splice predictor is SpliceAI; its maximum delta score is 0.015, below the PP3 threshold of 0.2 and the BP4 no-splice threshold of 0.1.

BP4 is not applicable because the VCEP silent-variant BP4 path requires an in-domain variant; BP7 computational Supporting likewise requires BP4, while BP7_Strong (RNA) needs an mRNA-only assay not available here.

Met · 1

BP1 StrongVCEPMet at Strong: silent variant outside all VCEP-defined domains with SpliceAI max delta 0.015, below the required ≤0.1 no-splicing threshold. Details ▾Hide ▴
Reasoning

The variant is a silent substitution at residue 1561, outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857). SpliceAI max delta is 0.015, satisfying the VCEP requirement of no predicted splicing (≤0.1). The VCEP therefore assigns BP1_Strong for a silent substitution outside a potentially clinically important functional domain without predicted splicing.

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). Missense prediction not applicable.
Evidence considered
  • Case consequence: synonymous/silent substitution c.4683C>G, p.(Thr1561=).
  • Residue 1561 is outside the VCEP-defined BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857 domains.
  • SpliceAI max delta score is 0.015, satisfying SpliceAI ≤0.1.
  • The VCEP BP1 rule expressly applies BP1_Strong to silent substitutions outside a potentially clinically important functional domain when no splicing is predicted; missense prediction is not applicable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗

Not met · 3 · evaluated, threshold not reached

PP3 VCEPNot met: SpliceAI maximum delta 0.015 is below the ENIGMA PP3 threshold of ≥0.2 for predicted splicing in silent variants. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_007294.4:c.4683C>G; p.(Thr1561=)). The ENIGMA BRCA1 rule permits PP3 for predicted splicing of silent variants when SpliceAI is ≥0.2. The case SpliceAI result is max delta 0.015, below the governing threshold, so PP3 is not met. No exact c.4683C>G, p.Thr1561=, or p.T1561= entry 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt; the similar c.4682C>T/p.(Thr1561Ile) entries are different variants and were not used.

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 donor and acceptor 1,2 sites.
Evidence considered
  • ENIGMA BRCA1 specification: PP3 applies to predicted splicing (SpliceAI ≥0.2) for silent variants irrespective of location in a clinically important functional domain.
  • SpliceAI Lookup for NM_007294.4:c.4683C>G: DS_AG 0.015, DS_AL 0.002, DS_DG 0.002, DS_DL 0.002; maximum delta score 0.015.
  • The governing VCEP full-text files were searched under all three supplied notations; no exact target-variant row was found. Similar c.4682C>T/p.(Thr1561Ile) rows in the supplementary materials were not treated as this variant.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_pmid_22505045_houdayer_2012_hummutat ↗
BA1 VCEPNot met: the variant was absent from gnomAD v2.1 and v3.1 non-cancer datasets, so no filter allele frequency exceeded the VCEP's 0.001 BA1 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP requires FAF above 0.001 in a specified non-founder gnomAD population for BA1. The case evidence records the synonymous variant NM_007294.4:c.4683C>G / p.Thr1561= as absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, so no qualifying FAF is present and BA1 is not met. The all-comers gnomAD v2.1 and v4.1 searches were also absent. No read-depth or QC failure was reported for the absent records, but absence alone cannot satisfy the BA1 frequency threshold.

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
  • gnomAD v2.1 non-cancer, exome-only search: NM_007294.4:c.4683C>G absent; no FAF reported.
  • gnomAD v3.1 non-cancer, genome-only search: NM_007294.4:c.4683C>G absent; no FAF reported.
  • ENIGMA BRCA1 Specifications v1.2, BA1 rule: FAF must be above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using a non-founder population.
Still missing
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot met: the variant was absent from gnomAD v2.1 and v3.1 non-cancer datasets, providing no filter allele frequency above the VCEP's 0.00002 BS1 lower threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP requires FAF above 0.0001 for BS1 Strong or above 0.00002 and at most 0.0001 for BS1 Supporting in the specified non-founder gnomAD populations. The case evidence records NM_007294.4:c.4683C>G / p.Thr1561= as absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, therefore neither BS1 frequency interval is met. The all-comers gnomAD v2.1 and v4.1 searches were also absent.

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
  • gnomAD v2.1 non-cancer, exome-only search: NM_007294.4:c.4683C>G absent; no FAF reported.
  • gnomAD v3.1 non-cancer, genome-only search: NM_007294.4:c.4683C>G absent; no FAF reported.
  • ENIGMA BRCA1 Specifications v1.2, BS1 rules: BS1 Strong requires FAF > 0.0001; BS1 Supporting requires FAF > 0.00002 and FAF <= 0.0001, in the specified non-founder gnomAD populations.
Still missing
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 12 · no assessment recorded

PS1 VCEPNot assessed: the synonymous variant has SpliceAI max delta 0.015, but no qualifying pathogenic comparator with a matching VCEP-defined splicing event is available. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_007294.4:c.4683C>G, p.(Thr1561=)); therefore the protein-change PS1 route does not apply. The VCEP permits PS1 for exonic variants with the same predicted splicing impact as an established pathogenic or likely pathogenic variant, but the available evidence contains no qualifying pathogenic comparator or matching predicted splicing event. SpliceAI max delta is 0.015, below the VCEP's 0.1 no-impact boundary, and the variant notation was not found in Specifications_Table4_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or Appendices_V1.2_2024-11-18.docx.

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
  • Case normalization: NM_007294.4:c.4683C>G produces NP_009225.1:p.(Thr1561=) / p.(T1561=), a synonymous substitution.
  • SpliceAI case result: max delta score 0.015 (DS_AG 0.015; DS_AL, DS_DG, and DS_DL 0.002), below the VCEP no-predicted-splicing boundary of 0.1.
  • The VCEP PS1 rule provides a protein-change route for predicted missense substitutions and a separate route for exonic or intronic variants with the same predicted splicing impact as a previously classified pathogenic or likely pathogenic variant; no qualifying comparator was available.
Still missing
  • No qualifying established pathogenic or likely pathogenic comparator with the same predicted splicing event was identified.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Appendices_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PS3 VCEPNot assessed: no calibrated damaging functional-assay result or pre-assigned PS3 strength was found for exact variant c.4683C>G. Details ▾Hide ▴
Reasoning

PS3 cannot be assessed because the exact variant NM_007294.4:c.4683C>G (p.Thr1561=; p.T1561=) has no calibrated functional-assay entry in Specifications_Table9_V1.2_2024-11-18.xlsx or SupplementaryTables_V1.2_2024-11-18.xlsx ST4. The exact variant was also not found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx. The nearby but different variant c.4682C>T was not used as evidence. Therefore, no variant-specific damaging protein-function result, assay controls, or calibrated PS3 strength is available under the ENIGMA BRCA1 V1.2 rules.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect ... Assay measures effect via protein only OR mRNA and protein combined. ... See Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • Specifications Table 9: searches for c.4683C>G, p.Thr1561=, and p.T1561= returned no exact-variant row; the displayed c.4682C>T row is a different variant and was excluded.
  • Supplementary Tables ST4: searches for c.4683C>G, p.Thr1561=, and p.T1561= returned no exact-variant functional-assay row; the displayed c.4682C>T row is a different variant and was excluded.
  • Specifications V1.2, Appendix E, and HUMU-40-1557-s001 were searched for all three notations and contained no exact-variant functional result.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4.
  • No exact-variant functional rule or result was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/Specifications_V1.2_2024-11-18.docx.txt.
  • No exact-variant functional rule or result was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/Appendices_V1.2_2024-11-18.docx.txt.
  • No exact-variant functional result was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
PS4 VCEPNot assessed: no matched case-control counts, odds ratio, confidence interval, p-value, or case-control likelihood ratio were available for c.4683C>G. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP requires case-control evidence with p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0. No ethnicity- and country-matched case/control counts, OR, confidence interval, p-value, or case-control likelihood ratio were available for NM_007294.4:c.4683C>G (p.Thr1561=). The literature_pass.json packet has an empty ai_classified_papers list; the only extracted candidate paper, PMID:12692171, does not mention BRCA1 or this variant and reports no case-control data. PS4 therefore 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).
Evidence considered
  • ENIGMA BRCA1 Specifications v1.2, PS4 rule: case-control studies require p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0; the case and control datasets should be ethnicity- and country-matched.
  • No entry for NM_007294.4:c.4683C>G, c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.txt, the governing PS4 file searched.
  • literature_pass.json contains ai_classified_papers: []; paper_extracts.json for PMID:12692171 states that the paper does not mention BRCA1 or c.4683C>G / p.(T1561=) and reports no case-control information.
Still missing
  • No matched case-control dataset with variant-positive case and control counts, OR, confidence interval, and p-value.
  • No case-control likelihood ratio.
  • The literature_pass.json ai_classified_papers list is empty; PMID:12692171 was extracted but does not mention this variant or case-control evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:12692171 ↗
PM2 VCEPNot assessed: the variant was absent from both required non-cancer gnomAD datasets, but the VCEP-required regional average read depth of at least 25 was not reported. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP permits PM2 Supporting when the variant is absent from controls in both gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average read depth at least 25 around the variant and acceptable QC. The case evidence records the variant as absent from both required non-cancer datasets, but provides no average regional read-depth value and no explicit QC metric. Because the VCEP makes read depth at least 25 a condition of application, PM2 cannot be assigned from absence alone.

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
  • gnomAD v2.1 non-cancer, exome-only search: NM_007294.4:c.4683C>G absent.
  • gnomAD v3.1 non-cancer, genome-only search: NM_007294.4:c.4683C>G absent.
  • ENIGMA BRCA1 Specifications v1.2, PM2 Supporting rule: absence from both required non-cancer datasets is required and the region around the variant must have average read depth >=25.
  • ENIGMA BRCA1 Appendices v1.2, Appendix G: PM2 Supporting uses read depth >25 and excludes data if the variant failed QC.
Still missing
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in HUMU-40-1557-s001.xlsx.txt.
  • Average read depth for the region around NM_007294.4:c.4683C>G is unavailable.
  • Explicit variant QC status for the required non-cancer gnomAD datasets is unavailable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
PM3 VCEPNot assessed: no qualifying Fanconi Anemia phenotype, same-gene co-occurring pathogenic variant, or affected-proband phase evidence is documented. Details ▾Hide ▴
Reasoning

The ENIGMA rule requires a patient with a phenotype consistent with BRCA1-related Fanconi Anemia and a co-occurrent variant in the same gene, with point assignment per proband in Table 6. The available case evidence does not document an affected proband with the required Fanconi Anemia phenotype, a same-gene pathogenic or likely pathogenic co-occurring variant, phase, or qualifying chromosome-breakage and clinical-feature observations. Therefore PM3 cannot be evaluated under the VCEP rule.

VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... 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
  • Specifications_V1.2_2024-11-18.docx.txt, PM3 rule: requires a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a co-occurrent variant in the same gene; Table 6 assigns points per proband.
  • Case evidence for NM_007294.4:c.4683C>G / p.Thr1561= contains no documented affected-proband Fanconi Anemia phenotype, chromosome-breakage result, same-gene pathogenic co-occurring variant, or phase observation.
Still missing
  • No variant-specific entry for c.4683C>G, p.Thr1561=, or p.T1561= was found when Specifications_V1.2_2024-11-18.docx.txt was searched.
  • Affected-proband Fanconi Anemia phenotype and chromosome-breakage results are not documented.
  • A same-gene pathogenic or likely pathogenic co-occurring variant and its phase with NM_007294.4:c.4683C>G are not documented.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP1 VCEPNot assessed: no quantitative affected-family co-segregation likelihood ratio is available to compare with the ENIGMA PP1 threshold of LR >=2.08:1. Details ▾Hide ▴
Reasoning

PP1 cannot be assessed because the available case evidence does not provide a quantitative co-segregation analysis, affected-family-member genotypes and phenotypes, meioses, or a co-segregation likelihood ratio for NM_007294.4:c.4683C>G. Under the ENIGMA rule, PP1 requires co-segregation in multiple affected family members measured by a quantitative method and assigns supporting evidence only at LR >=2.08:1. The required searches found no exact c.4683C>G, p.Thr1561=, or p.T1561= entry in either governing VCEP file.

VCEP rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details. ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1
Evidence considered
  • The available case evidence contains no quantitative co-segregation LR, pedigree-level segregation result, affected-family-member genotype set, or meiosis count for NM_007294.4:c.4683C>G.
  • ENIGMA PP1 requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation analysis method; PP1 supporting evidence requires LR >=2.08:1.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in HUMU-40-1557-s001.xlsx.txt.
  • No quantitative co-segregation likelihood ratio, pedigree-level affected-member genotypes, phenotypes, or meioses are documented for this variant.
Sources
cspec ↗
PP4 VCEPNot assessed: no variant-specific or combined multifactorial clinical likelihood ratio was available for comparison with the PP4 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP restricts PP4 to combined multifactorial clinical likelihood evidence and assigns Supporting evidence at LR ≥2.08:1, Moderate at LR ≥4.3:1, and Strong at LR ≥18.7:1. The governing Li et al. 2020 BRCA1 clinical-history LR table was searched for c.4683C>G and p.Thr1561= / p.T1561= and contains no matching row; no combined clinical LR was available elsewhere in the reviewed case evidence. PP4 cannot be evaluated.

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
Evidence considered
  • ENIGMA BRCA1 Specifications v1.2, PP4 rule: use only combined LR towards pathogenicity based on multifactorial likelihood clinical data; PP4 Supporting requires LR ≥2.08:1, PP4_Moderate LR ≥4.3:1, and PP4_Strong LR ≥18.7:1.
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.4683C>G, p.Thr1561=, and p.T1561=; no matching BRCA1 row was found.
  • The case evidence contains no combined clinical LR for this variant; no threshold comparison can therefore be made.
Still missing
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.4683C>G, p.Thr1561=, and p.T1561=; no matching row was found.
  • No combined multifactorial clinical LR from calibrated clinical data was available.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗
BS2 VCEPNot assessed: no qualifying phenotyped cohort observation, homozygote, or same-gene pathogenic-variant co-occurrence was available to assign the VCEP's BS2 points. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP applies BS2 using point assignments for phenotyped clinical or research-cohort individuals with the variant observed in trans with a pathogenic or likely pathogenic variant, as a homozygote, or with phase unknown alongside a pathogenic or likely pathogenic variant, and in the absence of Fanconi Anemia features. The available case evidence contains no qualifying healthy-adult clinical or research-cohort observation, no homozygote observation, no co-occurrence or phase information, and no BS2 point total. The VCEP specifically excludes unphenotyped gnomAD homozygote observations from BS2 frequency-code assessment.

VCEP rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Evidence considered
  • ENIGMA BRCA1 Specifications v1.2, Table 8: BS2 points depend on a phenotyped individual's presentation, including same-gene pathogenic-variant co-occurrence or homozygosity and age/cancer follow-up criteria.
  • ENIGMA BRCA1 Specifications v1.2, Table 8 footnote: BS2 homozygote points apply only to phenotyped clinical or research-cohort individuals and not to frequency-code data; gnomAD homozygotes are captured by BA1 or BS1.
  • No qualifying BS2 observation or point assignment was present in the case evidence.
Still missing
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in HUMU-40-1557-s001.xlsx.txt.
  • No qualifying phenotyped clinical or research-cohort BS2 observation, genotype phase, Fanconi Anemia assessment, or BS2 point total was available.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BS3 VCEPNot assessed: no calibrated benign functional-assay result or pre-assigned BS3 strength was found for exact variant c.4683C>G. Details ▾Hide ▴
Reasoning

BS3 cannot be assessed because the exact variant NM_007294.4:c.4683C>G (p.Thr1561=; p.T1561=) has no calibrated functional-assay entry in Specifications_Table9_V1.2_2024-11-18.xlsx or SupplementaryTables_V1.2_2024-11-18.xlsx ST4. The exact variant was also not found in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx. The nearby but different variant c.4682C>T was not used as evidence. Therefore, no variant-specific benign protein-function result, assay controls, or calibrated BS3 strength is available under the ENIGMA BRCA1 V1.2 rules.

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 Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • Specifications Table 9: searches for c.4683C>G, p.Thr1561=, and p.T1561= returned no exact-variant row; the displayed c.4682C>T row is a different variant and was excluded.
  • Supplementary Tables ST4: searches for c.4683C>G, p.Thr1561=, and p.T1561= returned no exact-variant functional-assay row; the displayed c.4682C>T row is a different variant and was excluded.
  • Specifications V1.2, Appendix E, and HUMU-40-1557-s001 were searched for all three notations and contained no exact-variant functional result.
Still missing
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No exact-variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4.
  • No exact-variant functional rule or result was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/Specifications_V1.2_2024-11-18.docx.txt.
  • No exact-variant functional rule or result was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/Appendices_V1.2_2024-11-18.docx.txt.
  • No exact-variant functional result was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/BRCA1/fulltext/HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
BS4 VCEPNot assessed: no quantitative non-segregation likelihood ratio is available to compare with the ENIGMA BS4 supporting threshold of LR <=0.48:1. Details ▾Hide ▴
Reasoning

BS4 cannot be assessed because the available case evidence does not provide a quantitative co-segregation analysis, affected-family-member genotypes and phenotypes, meioses, or a co-segregation likelihood ratio showing lack of segregation for NM_007294.4:c.4683C>G. Under the ENIGMA rule, BS4 requires lack of segregation measured by a quantitative co-segregation method; supporting evidence requires LR <=0.48:1. The required searches found no exact c.4683C>G, p.Thr1561=, or p.T1561= entry in either governing VCEP file.

VCEP rule
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48:1
Evidence considered
  • The available case evidence contains no quantitative non-segregation LR, pedigree-level affected-member genotype set, phenotype assessment, or meiosis count for NM_007294.4:c.4683C>G.
  • ENIGMA BS4 requires lack of segregation in affected family members measured by a quantitative co-segregation analysis method; BS4 supporting evidence requires LR <=0.48:1.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in HUMU-40-1557-s001.xlsx.txt.
  • No quantitative non-segregation likelihood ratio, pedigree-level affected-member genotypes, phenotypes, or meioses are documented for this variant.
Sources
cspec ↗
BP5 VCEPNot assessed: no variant-specific or combined clinical likelihood ratio was available for comparison with the BP5 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP permits BP5 only for combined multifactorial likelihood clinical data against pathogenicity, with Supporting evidence at LR ≤0.48 to >0.23:1, Moderate at LR ≤0.23:1, Strong at LR ≤0.05:1, and Very Strong at LR ≤0.00285:1. The governing Li et al. 2020 BRCA1 clinical-history LR table was searched for c.4683C>G and p.Thr1561= / p.T1561= and contains no matching row; no combined clinical LR was available. BP5 cannot be evaluated.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5 - LR ≤0.48 to >0.23:1
Evidence considered
  • ENIGMA BRCA1 Specifications v1.2, BP5 rule: use only combined LR against pathogenicity based on multifactorial likelihood clinical data; BP5 Supporting is LR ≤0.48 to >0.23:1, BP5_Moderate is LR ≤0.23:1, BP5_Strong is LR ≤0.05:1, and BP5_VeryStrong is LR ≤0.00285:1.
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.4683C>G, p.Thr1561=, and p.T1561=; no matching BRCA1 row was found.
  • No combined clinical LR was available, so no explicit BP5 inequality can be evaluated.
Still missing
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.4683C>G, p.Thr1561=, and p.T1561=; no matching row was found.
  • No combined multifactorial clinical LR against pathogenicity was available.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗
BP7 VCEPNot assessed: the outside-domain BP7_Strong (RNA) path requires an mRNA-only assay, but only SpliceAI maximum delta 0.015 is available. Details ▾Hide ▴
Reasoning

The variant is synonymous and outside the VCEP-defined clinically important functional domains. The ENIGMA BP7 Supporting computational path is specified for silent variants inside a clinically important functional domain if BP4 is met; BP4 is not applicable here. The VCEP separately allows BP7_Strong (RNA) for silent variants outside a clinically important functional domain, but that path requires a well-established mRNA-only functional assay. The available evidence contains only SpliceAI prediction (maximum delta 0.015) and no target-variant mRNA assay result, so BP7 cannot be assigned from the available evidence. No exact c.4683C>G, p.Thr1561=, or p.T1561= entry 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile – mRNA assay only. Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • ENIGMA BP7_Strong (RNA) rule: a well-established in vitro or in vivo functional study must show no damaging effect as measured by an mRNA transcript profile, using an mRNA-only assay; silent variants outside a clinically important functional domain are eligible for this path.
  • The available splice evidence is computational only: SpliceAI maximum delta score 0.015.
  • The governing VCEP full-text files were searched under all three supplied notations; no exact target-variant row was found.
Still missing
  • A well-established target-variant mRNA-only functional assay result is not available for the BP7_Strong (RNA) path.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_pmid_22505045_houdayer_2012_hummutat ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.4683C>G is synonymous (p.Thr1561=), whereas ENIGMA PVS1 applies to null variants; SpliceAI maximum delta is 0.015. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. The case variant is NM_007294.4:c.4683C>G, annotated as the synonymous change NP_009225.1:p.(Thr1561=) / p.(T1561=), not a null variant. It is also not at a canonical donor/acceptor +/-1,2 splice position, and the available SpliceAI maximum delta score is 0.015. The governing Table 4 search was performed for c.4683C>G, p.Thr1561=, and p.T1561=; no exact variant entry was found. Table 4 does show the BRCA1 E15(16) exon row with PVS1 for PTC and deletion/duplication paths, but those paths do not describe this synonymous substitution.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... See Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon.
Evidence considered
  • Case normalization: NM_007294.4:c.4683C>G; NP_009225.1:p.(Thr1561=) / p.(T1561=); consequence class synonymous; exon 15.
  • Specifications v1.2, PVS1_VariableWeight: 'Null variant in a gene where loss of function is a known mechanism of disease.'
  • Specifications v1.2, Table 4: BRCA1 E15(16) row assigns PVS1 to PTC and coding deletion/duplication paths, not to synonymous substitutions.
  • SpliceAI result: maximum delta score 0.015; the variant is not a canonical donor/acceptor +/-1,2 substitution.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗spliceai ↗
PS2 VCEPNot applicable: ENIGMA says de novo evidence is not calibrated for relatively common BRCA1/2-related cancers, regardless of parental testing. Details ▾Hide ▴
Reasoning

PS2 is not applicable under the ENIGMA BRCA1 VCEP specification. The VCEP states that BRCA1/2-related cancers occur relatively commonly and that there is no information to calibrate the predictive capacity of de novo occurrences. The required searches found no exact c.4683C>G, p.Thr1561=, or p.T1561= entry in either governing VCEP file.

VCEP rule
BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • The ENIGMA PS2 entry marks de novo evidence as not applicable because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.
  • Case normalization: NM_007294.4:c.4683C>G; NP_009225.1:p.(Thr1561=) / p.(T1561=).
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA explicitly says PM1 is not used, and residue 1561 lies outside its RING, coiled-coil, and BRCT domains. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly marks PM1 as not for use and directs the relevant domain/bioinformatic assessment to BP1, BP4, and PP3. Independently, residue 1561 lies outside the VCEP's clinically important domains: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857. No VCEP hotspot route is specified for this criterion.

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 VCEP PM1 entry states that PM1 is not used and that the relevant analysis is considered under BP1, BP4, and PP3.
  • The VCEP domain definitions are BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1561 is outside all three ranges.
  • The VCEP Appendix C catalogue lists the coiled-coil domain as aa 1391-1424 and BRCT domains as aa 1650-1863 in the structural discussion, while the clinical annotation summary defines the clinically important BRCT region as aa 1650-1857; either boundary places residue 1561 outside the domain.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM4 VCEPNot applicable: the variant is synonymous and causes no protein-length change, while ENIGMA PM4 is restricted to in-frame indels or stop-loss variants and says do not use. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the ENIGMA BRCA1 specification. The governing rule limits PM4 to protein-length changes from in-frame deletions/insertions in a non-repeat region or stop-loss variants, and the specification explicitly states 'Do not use'. This variant is synonymous and does not change protein length. The required searches found no exact c.4683C>G, p.Thr1561=, or p.T1561= entry in the named governing files.

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 normalization: NP_009225.1:p.(Thr1561=) / p.(T1561=), synonymous; no amino-acid or protein-length change.
  • Specifications v1.2 PM4 row: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' followed by 'Do not use'.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM5 N/ANot applicable: classic missense PM5 is not used by ENIGMA, and the synonymous variant is not a PVS1-eligible protein termination codon. Details ▾Hide ▴
Reasoning

The classic PM5 route concerns a missense change at a residue where a different pathogenic missense change has been observed, but the ENIGMA VCEP explicitly says not to use that route. Its repurposed PM5 (PTC) route is limited to protein termination codon variants annotated with PVS1; this variant is synonymous and does not create a PTC. No notation entry for this variant was found in the governing VCEP files searched.

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 ... 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 VCEP classic PM5 entry says not to use missense PM5 and directs evaluation to BP1, BP4, and PP3.
  • The VCEP repurposes PM5 only for a protein termination codon variant in an exon with a different proven pathogenic PTC, as additional weight for a PVS1-annotated variant.
  • Case consequence is synonymous, with protein result p.(Thr1561=), not a protein termination codon.
Still missing
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.4683C>G, p.Thr1561=, or p.T1561= was found in Appendices_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: ENIGMA says assumed de novo evidence is not calibrated for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

PM6 is not applicable under the ENIGMA BRCA1 VCEP specification. The VCEP states that BRCA1/2-related cancers occur relatively commonly and that there is no information to calibrate the predictive capacity of de novo occurrences. The required searches found no exact c.4683C>G, p.Thr1561=, or p.T1561= entry in either governing VCEP file.

VCEP rule
BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • The ENIGMA PM6 entry marks assumed de novo evidence without confirmed maternity and paternity as not applicable because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.
  • Case normalization: NM_007294.4:c.4683C>G; NP_009225.1:p.(Thr1561=) / p.(T1561=).
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA does not use PP2 because missense variants are not a common BRCA1 pathogenicity mechanism, and this variant is synonymous. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly says not to use PP2 because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2. The assessed variant is additionally synonymous rather than missense.

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 VCEP PP2 entry states Do not use and explains that missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.
  • Case normalization identifies c.4683C>G as synonymous, p.(Thr1561=).
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PP5 VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly says PP5 is not for use. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly states that PP5 is not for use. This criterion is not applicable regardless of the ClinVar submissions or literature leads for this synonymous variant.

VCEP rule
Do not use
Evidence considered
  • ENIGMA BRCA1 Specifications v1.2, PP5 entry: reputable-source pathogenic reports are listed, followed by the specification 'Do not use'.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP2 VCEPNot applicable: the VCEP explicitly says BP2 is not used and limits it to the BS2 context. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly states that BP2 is not to be used and is applied only in the context of BS2. Because the governing VCEP rule excludes BP2 as an independently applicable criterion, no phase or co-observation evidence can activate BP2 here.

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.txt, 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; Do not use; Applied only in the context of BS2.
Still missing
  • No variant-specific entry for c.4683C>G, p.Thr1561=, or p.T1561= was found when Specifications_V1.2_2024-11-18.docx.txt was searched.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP3 VCEPNot applicable: c.4683C>G is a synonymous substitution, not an in-frame deletion or insertion in a repetitive region, and ENIGMA BP3 says do not use. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the ENIGMA BRCA1 specification. The governing rule addresses only in-frame deletions/insertions in a repetitive region without a known function and explicitly states 'Do not use'; this variant is a synonymous single-nucleotide substitution, not an in-frame deletion or insertion. The required searches found no exact c.4683C>G, p.Thr1561=, or p.T1561= entry in the named governing files.

VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use
Evidence considered
  • Case normalization: NM_007294.4:c.4683C>G; NP_009225.1:p.(Thr1561=) / p.(T1561=); synonymous single-nucleotide substitution.
  • Specifications v1.2 BP3 row: 'In-frame deletions/insertions in a repetitive region without a known function' followed by 'Do not use'.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: p.Thr1561 lies outside ENIGMA's BRCA1 functional domains, while BP4's silent-variant path requires an in-domain variant. Details ▾Hide ▴
Reasoning

The variant is synonymous and encodes p.(Thr1561=). ENIGMA BP4's silent-variant path is limited to a silent variant inside a potentially clinically important functional domain. BRCA1 residue 1561 is outside the VCEP-defined coiled-coil domain (aa 1391-1424) and BRCT domain (aa 1650-1857), and is not in the RING domain (aa 2-101). Therefore BP4 is not applicable before evidence sufficiency is considered, even though SpliceAI is below 0.1. BayesDel is not relevant to this silent-variant path and no BayesDel score was used.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
  • ENIGMA BP4 rule: the silent-variant path requires a silent variant inside a potentially clinically important functional domain and SpliceAI ≤0.1.
  • ENIGMA functional-domain definitions: BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
  • The normalized protein consequence is NP_009225.1:p.(Thr1561=); residue 1561 is outside all three defined domains. SpliceAI maximum delta is 0.015, but that result cannot make an out-of-scope BP4 path applicable.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗
BP6 VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly says BP6 is not for use. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly states that BP6 is not for use. This criterion is not applicable regardless of the likely-benign ClinVar submissions or any reputable-source report.

VCEP rule
Do not use
Evidence considered
  • ENIGMA BRCA1 Specifications v1.2, BP6 entry: reputable-source benign reports are listed, followed by the specification 'Do not use'.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.4683C>G
Protein (HGVS p.)
NP_009225.1:p.(Thr1561=)
GRCh38
chr17:43071231 G>C
GRCh37
chr17:41223248 G>C
Location and type
Exon 15 · synonymous
ClinVar
868929, 868382, 865723, 865541, 438943, 420042, 55418, 37607

Gene diagram

Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.

BRCA1NM_007294.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +71 bp
0.002
SpliceAI acceptor gainat +5 bp
0.015
SpliceAI donor lossat -210 bp
0.002
SpliceAI donor gainat -368 bp
0.002
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.007

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta 0.015 is below the ENIGMA PP3 threshold of ≥0.2 for predicted splicing in silent variants. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_007294.4:c.4683C>G; p.(Thr1561=)). The ENIGMA BRCA1 rule permits PP3 for predicted splicing of silent variants when SpliceAI is ≥0.2. The case SpliceAI result is max delta 0.015, below the governing threshold, so PP3 is not met. No exact c.4683C>G, p.Thr1561=, or p.T1561= entry 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt; the similar c.4682C>T/p.(Thr1561Ile) entries are different variants and were not used.

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 donor and acceptor 1,2 sites.
Evidence considered
  • ENIGMA BRCA1 specification: PP3 applies to predicted splicing (SpliceAI ≥0.2) for silent variants irrespective of location in a clinically important functional domain.
  • SpliceAI Lookup for NM_007294.4:c.4683C>G: DS_AG 0.015, DS_AL 0.002, DS_DG 0.002, DS_DL 0.002; maximum delta score 0.015.
  • The governing VCEP full-text files were searched under all three supplied notations; no exact target-variant row was found. Similar c.4682C>T/p.(Thr1561Ile) rows in the supplementary materials were not treated as this variant.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_pmid_22505045_houdayer_2012_hummutat ↗
BP7 VCEPNot assessed: the outside-domain BP7_Strong (RNA) path requires an mRNA-only assay, but only SpliceAI maximum delta 0.015 is available. Details ▾Hide ▴
Reasoning

The variant is synonymous and outside the VCEP-defined clinically important functional domains. The ENIGMA BP7 Supporting computational path is specified for silent variants inside a clinically important functional domain if BP4 is met; BP4 is not applicable here. The VCEP separately allows BP7_Strong (RNA) for silent variants outside a clinically important functional domain, but that path requires a well-established mRNA-only functional assay. The available evidence contains only SpliceAI prediction (maximum delta 0.015) and no target-variant mRNA assay result, so BP7 cannot be assigned from the available evidence. No exact c.4683C>G, p.Thr1561=, or p.T1561= entry 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile – mRNA assay only. Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • ENIGMA BP7_Strong (RNA) rule: a well-established in vitro or in vivo functional study must show no damaging effect as measured by an mRNA transcript profile, using an mRNA-only assay; silent variants outside a clinically important functional domain are eligible for this path.
  • The available splice evidence is computational only: SpliceAI maximum delta score 0.015.
  • The governing VCEP full-text files were searched under all three supplied notations; no exact target-variant row was found.
Still missing
  • A well-established target-variant mRNA-only functional assay result is not available for the BP7_Strong (RNA) path.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_pmid_22505045_houdayer_2012_hummutat ↗
BP4 N/ANot applicable: p.Thr1561 lies outside ENIGMA's BRCA1 functional domains, while BP4's silent-variant path requires an in-domain variant. Details ▾Hide ▴
Reasoning

The variant is synonymous and encodes p.(Thr1561=). ENIGMA BP4's silent-variant path is limited to a silent variant inside a potentially clinically important functional domain. BRCA1 residue 1561 is outside the VCEP-defined coiled-coil domain (aa 1391-1424) and BRCT domain (aa 1650-1857), and is not in the RING domain (aa 2-101). Therefore BP4 is not applicable before evidence sufficiency is considered, even though SpliceAI is below 0.1. BayesDel is not relevant to this silent-variant path and no BayesDel score was used.

VCEP rule
Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
  • ENIGMA BP4 rule: the silent-variant path requires a silent variant inside a potentially clinically important functional domain and SpliceAI ≤0.1.
  • ENIGMA functional-domain definitions: BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
  • The normalized protein consequence is NP_009225.1:p.(Thr1561=); residue 1561 is outside all three defined domains. SpliceAI maximum delta is 0.015, but that result cannot make an out-of-scope BP4 path applicable.
Still missing
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.4683C>G, p.Thr1561=, or p.T1561= entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

6 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

  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    The paper does not explicitly mention BRCA1 or the exact variant c.4683C>G / NP_009225.1:p.(T1561=). It provides general ASCO policy recommendations for genetic testing of cancer-predisposition genes and reports no variant-specific case observations, case-control data, or benign/pathogenic source classification.
    Does not name this variant
    PMID 12692171 ↗
    Quoted passage
    ASCO recommends that genetic counseling and testing be offered when the 1) individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the genetic test can be adequately interpreted, and 3) the test results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.

    Indications for Genetic Testing for Cancer Susceptibility

  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    No paper-specific finding is recorded.
    PMID 17508274 ↗
  • American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
    Robson ME et al. · 2010
    No paper-specific finding is recorded.
    PMID 20065170 ↗
  • American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
    No paper-specific finding is recorded.
    PMID 26324357 ↗
  • PMID 31479213
    No paper-specific finding is recorded.
    PMID 31479213 ↗
  • 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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.015 Open source ↗
ClinVar 2 Likely benign · 1 Uncertain significance 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 420042)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.