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BRCA1c.1106_1108delBenign
Print report
Variant interpretation report

BRCA1 c.1106_1108del, p.Asp369del

NM_007294.4:c.1106_1108del NP_009225.1:p.(Asp369del) In frame indel unknown · exon 10 View identifiers
Classification
Benign

Variant description:

The BRCA1 NM_007294.4:c.1106_1108del (NP_009225.1:p.(Asp369del)) in-frame deletion variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: ENIGMA Table 9 reports protein function similar to benign controls in one calibrated study, with assay score 0.07. Based on available guidelines, this variant is considered to be Benign. This variant is considered to be Benign by the VCEP (Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA); ClinVar ID 54130).

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

Benign.A benign classification under the recorded framework.

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: 5
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 5
BS1Supporting
BS1 · supporting

Met at Supporting: gnomAD v2.1 non-cancer maximum FAF 0.00005945 falls between >0.00002 and <=0.0001.

BS3Strong
BS3 · strong

Met, Strong: ENIGMA Table 9 reports protein function similar to benign controls in one calibrated study, with assay score 0.07.

BS4Strong
BS4 · strong

Met, Strong: the segregation LR is 0.0116, below the ENIGMA BS4 Strong threshold of 0.05:1.

BP1Strong
BP1 · strong

Met at Strong: p.Asp369del is outside approved BRCA1 domains and SpliceAI maximum delta 0.068 is below the ENIGMA no-splicing threshold of 0.1.

BP6Supporting
BP6 · supporting

Not applicable: the ENIGMA BRCA1 specification explicitly states that BP6 is not to be used.

Recorded classification: Benign

Benign: BS3 Strong and BS4 Strong satisfy the ENIGMA rule requiring at least two Strong benign criteria, with additional BP1, BS1, and BP6 evidence.

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
156 / 1,614,042 alleles

gnomAD v4.1: 156 / 1,614,042 alleles. Recorded AF 9.66518e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 5.17586e-05; MAF= 0.00518%, 13/251166 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000114531; MAF= 0.01145%, 13/113506 alleles, homozygotes = 0); grpmax FAF= 6.675e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010860121633362293, 2/18416 alleles, homozygotes = 0).

Applied · BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.068 maximum delta

Recorded SpliceAI maximum delta score: 0.068. Refer to the recorded PP3/BP4 rationale for interpretation.

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

9 Likely benign · 3 Benign · 1 Uncertain significance. ClinVar API review status: reviewed by expert panel.

Applied · BP6 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

Applied · BS3 → 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: 5 met · 4 not met · 5 not assessed · 14 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 the ClinGen ENIGMA BRCA1 VCEP v1.2 rules: the variant is an in-frame p.Asp369del, PM4 and BP3 are explicitly not used, and PVS1 is restricted to null variant types.

Segregation/de novo group: PS2 and PM6 are not applicable because the ENIGMA VCEP explicitly prohibits their use; the quantitative segregation LR of 0.0116 does not meet PP1 but meets BS4 Strong (≤0.05:1).

The exact variant is pre-assigned BS3 Strong by the governing ENIGMA BRCA1 Specifications Table 9 based on a calibrated protein-function assay; no PS3 evidence is assigned.

Under the ClinGen ENIGMA BRCA1 VCEP v1.2 rules, PS4 is not assessed because no qualifying matched case-control comparison is available; PP4 and BP5 are not assessed because no eligible exact-variant multifactorial LR is available; PP5 and BP6 are not applicable because the VCEP says Do not use.

The exact variant was searched under c.1106_1108del, p.Asp369del, p.D369del, 1224delGAT, and 1225del3 in the governing files and extracted literature where applicable.

Met · 5

BS1 SupportingVCEPMet at Supporting: gnomAD v2.1 non-cancer maximum FAF 0.00005945 falls between >0.00002 and <=0.0001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP assigns BS1_Supporting when FAF is >0.00002 and <=0.0001 in the specified non-founder populations. The gnomAD v2.1 non-cancer exome maximum FAF is 0.00005945, within that interval; gnomAD v3.1 non-cancer genomes are lower at 0.00001171, but the VCEP rule uses and/or, so the qualifying v2.1 result supports BS1_Supporting.

VCEP rule
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 BS1_Supporting rule: 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).
  • gnomAD v2.1 non-cancer exomes: 11/236630 alleles, maximum non-cancer FAF 5.945e-05, which is >0.00002 and <=0.0001.
  • gnomAD v3.1 non-cancer genomes: maximum non-cancer FAF 1.171e-05, below the Supporting interval; this does not negate the qualifying v2.1 result under the VCEP's and/or wording.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 StrongVCEPMet, Strong: ENIGMA Table 9 reports protein function similar to benign controls in one calibrated study, with assay score 0.07. Details ▾Hide ▴
Reasoning

BS3 Strong is met by the governing ENIGMA Table 9 pre-assigned code for BRCA1 c.1106_1108del (p.(Asp369del)). The exact row states that one calibrated study reported protein function similar to benign control variants and assigns BS3 Strong, with assay score 0.07 and Bouwman 2020 (PMID:32546644) as the supporting study. This matches the VCEP BS3 rule for well-established functional studies showing no damaging effect on protein function when the assay measures protein only or mRNA and protein combined.

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.
Evidence considered
  • ENIGMA BRCA1 Specifications Table 9, row c.1106_1108del / p.(Asp369del): BS3 Strong; reported by one calibrated study to exhibit protein function similar to benign control variants; assay score 0.07; one study; Bouwman 2020 (PMID:32546644).
  • The VCEP Table 9 row is a pre-assigned code from the governing calibrated functional-assay table and therefore outranks any independently computed threshold.
  • The exact variant was searched in all five declared VCEP full-text files using c.1106_1108del, p.Asp369del, and p.D369del; the governing exact-variant functional assignment is BS3 Strong in Table 9.
Still missing
  • Specifications_V1.2_2024-11-18.docx.txt has no exact c.1106_1108del, p.Asp369del, or p.D369del variant row; its general BS3 rule was applied.
  • Appendices_V1.2_2024-11-18.docx.txt has no exact c.1106_1108del, p.Asp369del, or p.D369del variant row; its general functional-assay guidance was applied.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt and HUMU-40-1557-s001.xlsx.txt contain exact variant rows but do not provide an additional calibrated protein-function result for this BS3 assessment.
Sources
vcep_specifications_table9_v1_2_2024_11_18 ↗cspec ↗
BS4 StrongVCEPMet, Strong: the segregation LR is 0.0116, below the ENIGMA BS4 Strong threshold of 0.05:1. Details ▾Hide ▴
Reasoning

The ENIGMA multifactorial likelihood table reports a segregation LR of 0.0116 for BRCA1 c.1106_1108del (p.(Asp369del), D369del). The VCEP BS4 Strong threshold is LR ≤0.05:1; 0.0116 is below that threshold, so BS4 Strong is met.

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. ... BS4 - LR ≤0.05:1
Evidence considered
  • Parsons et al. 2019, HUMU-40-1557-s001, SuppT1 row BRCA1 c.1106_1108del / p.(Asp369del) / D369del: Segregation LR=0.0116; Combined LR=1.9495233660111288e-05; IARC class=Benign.
  • The ENIGMA BS4 rule assigns Strong weight at LR ≤0.05:1; the observed segregation LR of 0.0116 meets this threshold.
Sources
vcep_humu_40_1557_s001 ↗PMID:31131967 ↗cspec ↗
BP1 StrongVCEPMet at Strong: p.Asp369del is outside approved BRCA1 domains and SpliceAI maximum delta 0.068 is below the ENIGMA no-splicing threshold of 0.1. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion at p.Asp369del, outside all ENIGMA-defined potentially clinically important BRCA1 domains: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857. SpliceAI reports a maximum delta score of 0.068 (rounded in the case evidence to 0.07), below the VCEP's no-splicing threshold of ≤0.1. Therefore BP1_Strong applies.

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: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857; BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
Evidence considered
  • The variant is an in-frame deletion affecting residue 369.
  • The ENIGMA domain definition includes only BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 369 is outside each listed domain.
  • SpliceAI scores are DS_AG 0.001, DS_AL 0.000, DS_DG 0.068, and DS_DL 0.001; maximum delta score = 0.068, satisfying SpliceAI ≤0.1.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗spliceai ↗
BP6 SupportingVCEPNot applicable: the ENIGMA BRCA1 specification explicitly states that BP6 is not to be used. Details ▾Hide ▴
Reasoning

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

VCEP rule
Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 BP6 entry: reputable-source benign reports without independently evaluable evidence; the VCEP instruction is Do not use.
  • ClinVar expert panel classification
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

PS3 VCEPNot met: ENIGMA Table 9 assigns BS3 Strong because the calibrated protein-function assay score was 0.07 and resembled benign controls. Details ▾Hide ▴
Reasoning

PS3 is not met. The governing ENIGMA Table 9 row for BRCA1 c.1106_1108del (p.(Asp369del)) assigns BS3 Strong, not PS3, stating that one calibrated study reported protein function similar to benign control variants. The row identifies Bouwman 2020 (PMID:32546644), with assay score 0.07, and the VCEP reserves PS3 for well-established functional studies supportive of a damaging effect measured via protein or combined mRNA and protein. No conflicting damaging protein-function result is reported in the governing row.

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.
Evidence considered
  • ENIGMA BRCA1 Specifications Table 9, row c.1106_1108del / p.(Asp369del): BS3 Strong; reported by one calibrated study to exhibit protein function similar to benign control variants; assay score 0.07; Bouwman 2020 (PMID:32546644).
  • The exact variant was searched in all five declared VCEP full-text files using c.1106_1108del, p.Asp369del, and p.D369del; Table 9 provides the governing pre-assigned functional code.
  • The VCEP PS3 rule applies PS3 to well-established functional studies supportive of a damaging effect when the assay measures protein only or mRNA and protein combined; the governing exact-variant row does not report damaging effect.
Still missing
  • Specifications_V1.2_2024-11-18.docx.txt has no exact c.1106_1108del, p.Asp369del, or p.D369del variant row; its general PS3 rule was applied.
  • Appendices_V1.2_2024-11-18.docx.txt has no exact c.1106_1108del, p.Asp369del, or p.D369del variant row; its general functional-assay guidance was applied.
  • No PS3 assignment is present for this variant in Specifications_Table9_V1.2_2024-11-18.xlsx.txt; the exact Table 9 row assigns BS3 Strong instead.
Sources
vcep_specifications_table9_v1_2_2024_11_18 ↗cspec ↗
PP1 VCEPNot met: the segregation LR is 0.0116, below the ENIGMA PP1 Supporting threshold of 2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA multifactorial likelihood table reports a segregation LR of 0.0116 for BRCA1 c.1106_1108del (p.(Asp369del), D369del). This is below the VCEP PP1 Supporting threshold of LR ≥2.08:1 and therefore does not support co-segregation evidence for PP1.

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. ... PP1 - LR ≥2.08:1
Evidence considered
  • Parsons et al. 2019, HUMU-40-1557-s001, SuppT1 row BRCA1 c.1106_1108del / p.(Asp369del) / D369del: Segregation LR=0.0116; Combined LR=1.9495233660111288e-05; IARC class=Benign.
  • The ENIGMA PP1 rule assigns Supporting weight only at LR ≥2.08:1; the observed segregation LR of 0.0116 does not meet that threshold.
Sources
vcep_humu_40_1557_s001 ↗PMID:31131967 ↗cspec ↗
PP3 VCEPNot met: SpliceAI maximum delta 0.068 is below the VCEP PP3 splice-impact threshold of 0.2, and residue 369 lies outside the protein-impact domains. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion, p.(Asp369del), at amino acid 369. The VCEP's protein-impact PP3 path applies only inside a potentially clinically important functional domain; BRCA1 residue 369 is outside the specified RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, so that path is not applicable. The VCEP's splice-impact PP3 path does apply to in-frame variants irrespective of functional-domain location, but requires SpliceAI >=0.2. The case-specific SpliceAI maximum delta score is 0.068 (reported as 0.07), below that threshold. No PP3 code is pre-assigned for this variant in the searched ENIGMA supplementary tables. Therefore PP3 is not met.

VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). ... 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
  • Case normalization identifies NM_007294.4:c.1106_1108del as NP_009225.1:p.(Asp369del), an in-frame deletion at amino acid 369.
  • ENIGMA Specifications v1.2, PP3: the protein-impact path is limited to missense or in-frame insertion/deletion/delins variants inside a potentially clinically important functional domain and requires BayesDel no-AF >=0.28; the defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857, so p.Asp369del is outside that path.
  • ENIGMA Specifications v1.2, PP3: the splice-impact path applies to silent and missense/in-frame variants irrespective of functional-domain location when SpliceAI >=0.2.
  • Case SpliceAI result for NM_007294.4:c.1106_1108del: DS_AG 0.001, DS_AL 0.000, DS_DG 0.068, DS_DL 0.001; maximum delta 0.068, summarized as 0.07.
  • Search of SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.1106_1108del, p.Asp369del, and p.D369del found the variant in ST1-related frequency/multifactorial content but no pre-assigned PP3 code.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗spliceai ↗
BA1 VCEPNot met: maximum non-cancer FAF was 0.00005945, below the ENIGMA BA1 threshold of >0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP requires FAF >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The maximum reported non-cancer FAF is 0.00005945 in gnomAD v2.1 non-cancer exomes and 0.00001171 in gnomAD v3.1 non-cancer genomes, both below 0.001; therefore BA1 is not met.

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 BA1 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).
  • gnomAD v2.1 non-cancer exomes: 11/236630 alleles, AF 4.6486075307442e-05, maximum non-cancer FAF 5.945e-05, homozygotes 0.
  • gnomAD v3.1 non-cancer genomes: 4/147944 alleles, AF 2.703725734061537e-05, maximum non-cancer FAF 1.171e-05, homozygotes 0.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS4 VCEPNot assessed: exact-variant reports lack an ethnicity-matched control comparison and the counts needed to test p-value <=0.05, OR >=4, and lower CI >2.0. Details ▾Hide ▴
Reasoning

The ENIGMA rule requires a case-control study with p-value <=0.05, OR >=4, and a lower confidence limit excluding 2.0. The reviewed exact-variant reports document one affected individual in a population-based breast-cancer series (PMID:11044354) and observations in a clinical-testing cohort (PMID:16267036), but neither supplies an ethnicity-matched unaffected/control comparison or sufficient 2x2 counts to calculate an OR, 95% CI, and p-value. PMID:17924331 was searched and does not mention this variant. Therefore PS4 cannot be evaluated from the available evidence.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. ... Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 PS4: case-control studies require p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0; the case dataset should be ethnicity- and country-matched to the control dataset.
  • PMID:11044354, exact variant reported as 1224delGAT (D369del) in one woman diagnosed with breast cancer at age 53; the paper states the variant was excluded from its mutation-prevalence analysis, so no usable control comparison is provided.
  • PMID:16267036, Table 4 reports D369del (1225del3) in trans with 5385insC and Table 2 reports occurrence 8-19 times in a 55,630-patient clinical-testing dataset; no unaffected/control denominator or variant-specific case-control analysis is reported.
  • PMID:17924331 was searched for c.1106_1108del, p.(D369del), and D369del; its paper_extracts finding states that the exact variant is not mentioned.
Still missing
  • No ethnicity- and country-matched case-control dataset with c.1106_1108del/p.(D369del) case and control counts was found in PMID:11044354 or PMID:16267036.
  • PMID:17924331 was searched for c.1106_1108del, p.(D369del), and D369del; no entry for this variant was found.
  • literature_pass.json has no ai_classified_papers entries to verify for PS4.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:11044354 ↗PMID:16267036 ↗PMID:17924331 ↗
PM3 VCEPNot assessed: D369del was reported in trans with BRCA1 5385insC, but the required Fanconi Anemia phenotype and Table 6 point-assigning observations are unavailable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP restricts PM3 to a patient with phenotype consistent with BRCA1-related Fanconi Anemia and a co-occurrent variant in the same gene, with points assigned from Table 6. PMID:16267036 reports D369del (1225del3) observed in trans with the known deleterious BRCA1 variant 5385insC, but the available case evidence does not document the required Fanconi Anemia phenotype, chromosome-breakage result, or qualifying clinical features. Therefore the VCEP PM3 rule cannot be evaluated; the trans observation alone is insufficient. The governing Specifications_V1.2_2024-11-18.docx was searched for c.1106_1108del, p.Asp369del, and p.D369del and contains no variant-specific PM3 entry; its general PM3 rule and Table 6 govern.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant. ... 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 Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. ... For related individuals score only most severe presentation.
Evidence considered
  • Judkins et al. 2005 (PMID:16267036), Table 4 heterozygous-haplotype row: D369del (1225del3) observed with the known deleterious BRCA1 variant 5385insC; the source reports this as a trans observation but does not provide the VCEP-required Fanconi Anemia phenotype assessment.
  • ENIGMA BRCA1 VCEP Specifications v1.2, Table 1 PM3 entry and Table 6: PM3 requires a BRCA1/2-related Fanconi Anemia phenotype with a co-occurrent same-gene variant, and final strength is based on PM3-related points across qualifying probands.
Still missing
  • No qualifying Fanconi Anemia phenotype, chromosome-breakage result, or clinical features meeting the VCEP PM3 definition are documented for the affected individual(s).
  • Specifications_V1.2_2024-11-18.docx was searched for c.1106_1108del, p.Asp369del, and p.D369del; no variant-specific PM3 entry was found, so the general VCEP PM3 rule and Table 6 were applied.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:16267036 ↗
PP4 VCEPNot assessed: no eligible exact-variant combined clinical LR was found to test the ENIGMA PP4 thresholds of >=2.08, >=4.3, >=18.7, or >=350. Details ▾Hide ▴
Reasoning

The ENIGMA rule permits PP4 only for a combined multifactorial clinical likelihood ratio and requires LR >=2.08:1 for Supporting, >=4.3:1 for Moderate, >=18.7:1 for Strong, or >=350:1 for Very Strong. The governing Li et al. clinical-history LR file was searched for exact Gene=BRCA1 and c.1106_1108del/p.(D369del), but no row was found; the Easton paper was also searched and its extraction states that the exact variant is not mentioned. The exact variant's row in HUMU-40-1557-s001 is not a PP4/BP5-declared source under the VCEP index, so it is not substituted for the governing PP4 evidence. No eligible combined LR is therefore available.

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 ... PP4_Moderate – LR≥4.3:1 ... PP4_Strong – LR≥18.7:1 ... PP4_Very Strong – LR≥350:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 PP4: use only to capture combined LR towards pathogenicity based on multifactorial likelihood clinical data; thresholds are PP4 Supporting LR >=2.08:1, Moderate LR >=4.3:1, Strong LR >=18.7:1, and Very Strong LR >=350:1.
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched by exact Gene=BRCA1 and the three supplied variant notations; no exact variant row or pre-assigned LR was found.
  • PMID:17924331 paper_extracts reports that c.1106_1108del, p.(D369del), and D369del were searched and the exact variant was not mentioned.
  • HUMU-40-1557-s001.xlsx contains an exact-variant multifactorial row, but the BRCA1 VCEP index declares that file for BS4, PS3, BS3, and PM2, not PP4 or BP5; it was not used to override the PP4-declared sources.
Still missing
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for BRCA1 c.1106_1108del, p.Asp369del, and p.D369del; no exact row was found.
  • PMID_17924331_Easton_2007_AJHG.pdf was searched for c.1106_1108del, p.(D369del), and D369del; no exact variant entry was found.
  • No other PP4-declared source provides an eligible exact-variant combined multifactorial LR.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗vcep_pmid_17924331_easton_2007_ajhg ↗PMID:17924331 ↗
BS2 VCEPNot assessed: gnomAD reports zero homozygotes, while no qualifying phenotyped healthy-adult observation or BS2 point assignment is available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP requires observation in a healthy adult individual and assigns strength from qualifying BS2-related proband points in Table 8. The available population data show zero homozygotes, and the VCEP explicitly excludes frequency data used for BA1 or BS1 from BS2; no qualifying phenotyped healthy-adult proband observation or BS2 point assignment is available.

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 BS2 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.
  • ENIGMA Appendix H states that BS2 is not to be applied to data used to assign frequency-based codes; variants observed as >=2 homozygotes in gnomAD are already captured by BA1 or BS1 frequency codes.
  • gnomAD v2.1 and gnomAD v4.1 report zero homozygotes for this variant; the case materials contain no qualifying phenotyped healthy-adult BS2 proband or Table 8 point assignment.
Still missing
  • No qualifying phenotyped healthy-adult proband observation and no ENIGMA Table 8 BS2 point assignment were found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
BP5 VCEPNot assessed: no eligible exact-variant LR was found to test BP5's required downward inequalities, including LR <=0.48, <=0.23, <=0.05, or <=0.00285. Details ▾Hide ▴
Reasoning

The ENIGMA rule restricts BP5 to a combined multifactorial clinical LR against pathogenicity and requires LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, or <=0.00285 for Very Strong. The required direction is downward: no eligible exact-variant LR was found in the PP4/BP5-declared Li clinical-history table, and PMID:17924331 does not mention the exact variant. The exact row in HUMU-40-1557-s001 is not from a BP5-declared file under the VCEP index and was not used.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5_VeryStrong - LR ≤0.00285:1 ... BP5_Strong - LR ≤0.05:1 ... BP5_Moderate - LR ≤0.23:1 ... BP5 - LR ≤0.48 to >0.23:1
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 BP5: use only to capture combined LR against pathogenicity based on multifactorial likelihood clinical data; thresholds are BP5 Supporting LR <=0.48 to >0.23, Moderate LR <=0.23, Strong LR <=0.05, and Very Strong LR <=0.00285.
  • Explicit inequality check required by the VCEP rule cannot be performed because no eligible exact-variant LR is available: LR <=0.48?, LR <=0.23?, LR <=0.05?, and LR <=0.00285? are all not evaluable.
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched by exact Gene=BRCA1 and the three supplied variant notations; no exact variant row or pre-assigned LR was found.
  • PMID:17924331 paper_extracts reports that c.1106_1108del, p.(D369del), and D369del were searched and the exact variant was not mentioned.
  • HUMU-40-1557-s001.xlsx contains an exact-variant multifactorial row, but the BRCA1 VCEP index does not declare that file for BP5; it was not used as BP5 evidence.
Still missing
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for BRCA1 c.1106_1108del, p.Asp369del, and p.D369del; no exact row was found.
  • PMID_17924331_Easton_2007_AJHG.pdf was searched for c.1106_1108del, p.(D369del), and D369del; no exact variant entry was found.
  • No eligible BP5-declared source provides an exact-variant combined multifactorial LR.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗vcep_pmid_17924331_easton_2007_ajhg ↗PMID:17924331 ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.1106_1108del is a three-nucleotide in-frame p.Asp369del, not one of the VCEP-defined null variant types eligible for PVS1. Details ▾Hide ▴
Reasoning

NM_007294.4:c.1106_1108del produces NP_009225.1:p.(Asp369del), a three-nucleotide in-frame deletion in BRCA1 exon 10 (legacy exon 11), not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion null variant. The ENIGMA Table 4 search was performed using c.1106_1108del, p.Asp369del, and p.D369del; no variant-specific PVS1 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt. The VCEP PVS1 rule is restricted to null variants and directs exon-specific application through Table 4 and Appendix D, so PVS1 is not applicable.

VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5 (PTC) code (see description below).
Evidence considered
  • Variant normalization: NM_007294.4:c.1106_1108del -> NP_009225.1:p.(Asp369del)/p.(D369del); consequence class is in_frame_indel_unknown.
  • Specifications Table 4, BRCA1 exon 10(11) rows: the exon coding interval is c.671-c.4096 and the protein interval is p.224-p.1366; the table provides PVS1 decisions for initiation, PTC, exon deletion/duplication, and canonical splice-site variants, not this in-frame deletion.
  • Specifications Table 4 full-text search for c.1106_1108del, p.Asp369del, and p.D369del: no matching entry found.
Still missing
  • No entry for c.1106_1108del, p.Asp369del, or p.D369del was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
pvs1_variant_assessmentcspec ↗vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗
PS1 N/ANot applicable: p.(Asp369del) is an in-frame deletion, whereas ENIGMA PS1 requires a predicted missense substitution or precisely matching pathogenic splicing event. Details ▾Hide ▴
Reasoning

The queried variant is an in-frame deletion, p.(Asp369del), not a predicted missense substitution. The ENIGMA PS1 rule is restricted to same-protein missense substitutions or variants with the same predicted splicing impact as a known (likely) pathogenic variant; no qualifying same-protein missense or same-splicing comparison is available for this deletion.

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
  • Variant normalization: NM_007294.4:c.1106_1108del produces NP_009225.1:p.(Asp369del), an in-frame deletion.
  • No governing VCEP table entry establishing a same-protein pathogenic missense substitution or a precisely matching pathogenic splice event was identified for this deletion.
  • The governing ENIGMA specification limits PS1 to predicted missense substitutions or variants with the same predicted splicing impact as a previously classified (likely) pathogenic variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PS2 VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly says PS2 is not used for de novo occurrences in BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly states that PS2 should not be used because BRCA1/2-related cancers occur relatively commonly and there is 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 BRCA1 specification v1.2, PS2: de novo occurrence is explicitly designated Do not use; the specification gives no calibrated use for this criterion.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA says PM1 is not used, and residue 369 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly states that PM1 is not to be used and that hotspot or functional-domain information is considered within PP3/BP4 instead. Independently, residue 369 is outside the ENIGMA-defined BRCA1 RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857); the reviewed Easton report also states that the deleted amino acid does not lie within a known functional domain.

VCEP rule
Do not use Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • The ENIGMA specification's PM1 entry says: Do not use; hotspot and critical-domain information is considered as a component of PP3/BP4.
  • The governing BRCA1 domain definition lists RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.(Asp369del) is at residue 369 and is outside all three.
  • Easton et al. 2000 reports for 1224delGAT (D369del): the deleted amino acid does not lie within any known functional domain.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗PMID:11044354 ↗
PM2 N/ANot applicable: ENIGMA excludes PM2 for deletion variants, and this variant is an in-frame deletion present in both specified datasets. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification states that PM2 should not be applied for deletion variants. This variant is c.1106_1108del, an in-frame deletion, so PM2 is not applicable regardless of its observed rarity; the variant is also present in both specified non-cancer datasets.

VCEP rule
Do not apply for insertion, deletion or delins variants.
Evidence considered
  • ENIGMA PM2 rule identifies gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes as the preferred datasets, and the governing specification states: Do not apply for insertion, deletion or delins variants.
  • The variant is NM_007294.4:c.1106_1108del / NP_009225.1:p.(Asp369del), classified in the case data as an in-frame deletion.
  • gnomAD v2.1 non-cancer exomes: AF 4.6486075307442e-05 (11/236630 alleles); gnomAD v3.1 non-cancer genomes: AF 2.703725734061537e-05 (4/147944 alleles).
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗gnomad_v4 ↗
PM4 VCEPNot applicable: although p.Asp369del changes protein length, the BRCA1 VCEP explicitly says PM4 is not used for this framework. Details ▾Hide ▴
Reasoning

The variant is a three-nucleotide in-frame deletion causing p.(Asp369del), but the BRCA1 VCEP explicitly specifies PM4 as do not use and states that this evidence is considered as a component of bioinformatic analysis (PP3/BP4), which is outside this requested group. Therefore PM4 is not applicable under the governing VCEP rules.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Do not use Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • The case consequence assessment identifies c.1106_1108del as an in-frame deletion producing p.(Asp369del).
  • Easton et al. 2007 (PMID:11044354), Results paragraph describing in-frame deletions: the variant is reported as 1224delGAT (D369del), and the deleted amino acid is outside any known functional domain; the authors considered its functional significance uncertain.
  • The VCEP specification Table 1 lists PM4 as 'Do not use' and says it is considered as a component of bioinformatic analysis (PP3/BP4).
Sources
pvs1_variant_assessmentcspec ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:11044354 ↗
PM5 N/ANot applicable: ENIGMA does not use ordinary missense PM5, and PM5_PTC is restricted to protein-termination-codon variants annotated PVS1. Details ▾Hide ▴
Reasoning

The ordinary missense PM5 route is explicitly not used by the ENIGMA VCEP. The only retained PM5 route is PM5_VariableWeight (PTC), which applies only to protein-termination-codon variants annotated as PVS1; p.(Asp369del) is an in-frame deletion, not a PTC variant.

VCEP rule
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 ENIGMA PM5 entry says the missense PM5 criterion is not used and is considered within PP3/BP4.
  • The ENIGMA PM5_PTC route is limited to protein termination codon variants in an exon where a different proven pathogenic PTC variant has been seen and is used for additional weight for PVS1 variants.
  • The variant is c.1106_1108del, p.(Asp369del), an in-frame deletion rather than a PTC variant; the Table 4 PTC decision table therefore does not govern this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the ENIGMA BRCA1 VCEP explicitly says PM6 is not used for uncalibrated de novo occurrences. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly states that PM6 should not be used because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences without confirmed parental testing.

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 BRCA1 specification v1.2, PM6: confirmed de novo without confirmation of paternity and maternity is explicitly designated Do not use.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA says PP2 is not used for BRCA1, which has a high frequency of benign missense variants, and this variant is an in-frame deletion. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly says not to use PP2 because BRCA1 has a high frequency of benign missense variants. In addition, this variant is an in-frame deletion rather than a missense variant.

VCEP rule
Do not use High frequency of benign missense variants.
Evidence considered
  • The ENIGMA PP2 entry says Do not use and gives high frequency of benign missense variants as the reason.
  • Variant normalization identifies p.(Asp369del), an in-frame deletion rather than a missense substitution.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP5 VCEPNot applicable: the ENIGMA BRCA1 specification explicitly states that PP5 is not to be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly says not to use PP5. This criterion is therefore not applicable regardless of benign or pathogenic reports in ClinVar or other reputable sources.

VCEP rule
Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 1 PP5 entry: reputable-source pathogenic reports without independently evaluable evidence; the VCEP instruction is Do not use.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP2 VCEPNot applicable: the VCEP explicitly says BP2 is not used and permits it only in the context of BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly says not to use BP2 and limits it to the context of BS2. BP2 is therefore not applicable under the governing VCEP specification, regardless of the reported trans observation.

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
  • ENIGMA BRCA1 VCEP Specifications v1.2, Table 1 BP2 row: observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant, followed by 'Do not use' and 'Applied only in the context of BS2.'
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP3 VCEPNot applicable: despite being an in-frame deletion, BP3 is explicitly excluded by the BRCA1 VCEP and captured through bioinformatic/domain analysis instead. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion, but the BRCA1 VCEP explicitly specifies BP3 as do not use and directs that this type of evidence is captured by bioinformatic tool prediction and domain analysis rather than BP3. Therefore BP3 is not applicable under the governing VCEP rules.

VCEP rule
In-frame deletions/insertions in a repetitive region without a known function Do not use Captured by bioinformatic tool prediction, and domain analysis. See Appendix J.
Evidence considered
  • The case consequence assessment identifies c.1106_1108del as an in-frame deletion producing p.(Asp369del).
  • The VCEP specification Table 1 lists BP3 for in-frame deletions/insertions in repetitive regions without known function as 'Do not use' and states that it is captured by bioinformatic tool prediction and domain analysis.
Sources
pvs1_variant_assessmentcspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: p.Asp369del is outside the VCEP-defined functional domains required for BP4 on an in-frame deletion, despite SpliceAI maximum delta 0.068. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion at p.Asp369del. Under the VCEP rule, BP4 for an in-frame deletion requires the variant to be inside a potentially clinically important functional domain and requires both BayesDel no-AF <=0.15 and SpliceAI <=0.1. Residue 369 is outside the VCEP-defined BRCA1 RING, coiled-coil, and BRCT domains. Thus the in-frame-deletion BP4 path is outside scope, regardless of the available SpliceAI maximum delta score of 0.068; BP4 is not applicable rather than assessed as met from splice prediction alone. No BP4 code is pre-assigned for this variant in the searched ENIGMA supplementary tables.

VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1). ... Missense Predictions (BayesDel no AF) BRCA1: No impact ≤ 0.15
Evidence considered
  • Case normalization identifies NM_007294.4:c.1106_1108del as NP_009225.1:p.(Asp369del), an in-frame deletion at amino acid 369.
  • ENIGMA Specifications v1.2, BP4: the in-frame insertion/deletion/delins path requires location inside a potentially clinically important functional domain, BayesDel no-AF <=0.15, and SpliceAI <=0.1.
  • ENIGMA Appendix J defines the BRCA1 domains used for this analysis as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 369 is outside all three.
  • Case SpliceAI result: maximum delta 0.068, with DS_DG 0.068 and all other delta scores <=0.001; this does not change the criterion's domain-based non-applicability.
  • Search of SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.1106_1108del, p.Asp369del, and p.D369del found no pre-assigned BP4 code for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗spliceai ↗
BP7 N/ANot applicable: BP7 covers silent or qualifying intronic variants, whereas this variant is an in-frame deletion, regardless of its SpliceAI maximum delta 0.068. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion, not a synonymous (silent) or intronic variant. The VCEP BP7 rule is limited to silent variants inside a potentially clinically important functional domain or intronic variants outside conserved donor/acceptor motif positions, with BP4 met. Neither BP7 applicability path covers this in-frame deletion. The SpliceAI maximum delta score of 0.068 cannot make BP7 applicable. No BP7 code is pre-assigned for this variant in the searched ENIGMA supplementary tables.

VCEP rule
Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
Evidence considered
  • Case normalization identifies NM_007294.4:c.1106_1108del as NP_009225.1:p.(Asp369del), an in-frame deletion.
  • ENIGMA Specifications v1.2, BP7 applies to silent variants inside a potentially clinically important functional domain if BP4 is met, and to intronic variants outside conserved donor or acceptor motif positions if BP4 is met; it does not include in-frame deletions.
  • Case SpliceAI result: maximum delta 0.068 (DS_DG 0.068), which is not a basis for extending BP7 beyond the variant types named by the VCEP.
  • Search of SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.1106_1108del, p.Asp369del, and p.D369del found no pre-assigned BP7 code for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗spliceai ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.1106_1108del
Protein (HGVS p.)
NP_009225.1:p.(Asp369del)
GRCh38
chr17:43094422 ACAT>A
GRCh37
chr17:41246439 ACAT>A
Location and type
Exon 10 · in frame indel unknown
ClinVar
54130

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 v4.1 156 / 1,614,042 alleles AF 9.67e-05 · 0 homozygotes · FAF 0.000108
gnomAD v2.1 13 / 251,166 alleles AF 5.18e-05 · 0 homozygotes · FAF 6.67e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 9.7e-05 · 156 / 1,614,042 alleles · 0 hom · FAF 0.00011
European (non-Finnish)147 / 1,180,044 0.00012
Remaining individuals7 / 62,486 0.00011
African/African American2 / 74,928 2.7e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 5.2e-05 · 13 / 251,166 alleles · 0 hom · FAF 6.7e-05
European (non-Finnish)13 / 113,506 0.00011
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 9.66518e-05; MAF= 0.00967%, 156/1614042 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000124572; MAF= 0.01246%, 147/1180044 alleles, homozygotes = 0); grpmax FAF= 0.00010792.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 5.17586e-05; MAF= 0.00518%, 13/251166 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000114531; MAF= 0.01145%, 13/113506 alleles, homozygotes = 0); grpmax FAF= 6.675e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010860121633362293, 2/18416 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +473 bp
0.000
SpliceAI acceptor gainat -342 bp
0.001
SpliceAI donor lossat -145 bp
0.001
SpliceAI donor gainat +322 bp
0.068
Pangolin splice lossmagnitude shown
-0.052
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta 0.068 is below the VCEP PP3 splice-impact threshold of 0.2, and residue 369 lies outside the protein-impact domains. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion, p.(Asp369del), at amino acid 369. The VCEP's protein-impact PP3 path applies only inside a potentially clinically important functional domain; BRCA1 residue 369 is outside the specified RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, so that path is not applicable. The VCEP's splice-impact PP3 path does apply to in-frame variants irrespective of functional-domain location, but requires SpliceAI >=0.2. The case-specific SpliceAI maximum delta score is 0.068 (reported as 0.07), below that threshold. No PP3 code is pre-assigned for this variant in the searched ENIGMA supplementary tables. Therefore PP3 is not met.

VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). ... 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
  • Case normalization identifies NM_007294.4:c.1106_1108del as NP_009225.1:p.(Asp369del), an in-frame deletion at amino acid 369.
  • ENIGMA Specifications v1.2, PP3: the protein-impact path is limited to missense or in-frame insertion/deletion/delins variants inside a potentially clinically important functional domain and requires BayesDel no-AF >=0.28; the defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857, so p.Asp369del is outside that path.
  • ENIGMA Specifications v1.2, PP3: the splice-impact path applies to silent and missense/in-frame variants irrespective of functional-domain location when SpliceAI >=0.2.
  • Case SpliceAI result for NM_007294.4:c.1106_1108del: DS_AG 0.001, DS_AL 0.000, DS_DG 0.068, DS_DL 0.001; maximum delta 0.068, summarized as 0.07.
  • Search of SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.1106_1108del, p.Asp369del, and p.D369del found the variant in ST1-related frequency/multifactorial content but no pre-assigned PP3 code.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗spliceai ↗
BP4 N/ANot applicable: p.Asp369del is outside the VCEP-defined functional domains required for BP4 on an in-frame deletion, despite SpliceAI maximum delta 0.068. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion at p.Asp369del. Under the VCEP rule, BP4 for an in-frame deletion requires the variant to be inside a potentially clinically important functional domain and requires both BayesDel no-AF <=0.15 and SpliceAI <=0.1. Residue 369 is outside the VCEP-defined BRCA1 RING, coiled-coil, and BRCT domains. Thus the in-frame-deletion BP4 path is outside scope, regardless of the available SpliceAI maximum delta score of 0.068; BP4 is not applicable rather than assessed as met from splice prediction alone. No BP4 code is pre-assigned for this variant in the searched ENIGMA supplementary tables.

VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1). ... Missense Predictions (BayesDel no AF) BRCA1: No impact ≤ 0.15
Evidence considered
  • Case normalization identifies NM_007294.4:c.1106_1108del as NP_009225.1:p.(Asp369del), an in-frame deletion at amino acid 369.
  • ENIGMA Specifications v1.2, BP4: the in-frame insertion/deletion/delins path requires location inside a potentially clinically important functional domain, BayesDel no-AF <=0.15, and SpliceAI <=0.1.
  • ENIGMA Appendix J defines the BRCA1 domains used for this analysis as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 369 is outside all three.
  • Case SpliceAI result: maximum delta 0.068, with DS_DG 0.068 and all other delta scores <=0.001; this does not change the criterion's domain-based non-applicability.
  • Search of SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.1106_1108del, p.Asp369del, and p.D369del found no pre-assigned BP4 code for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗spliceai ↗
BP7 N/ANot applicable: BP7 covers silent or qualifying intronic variants, whereas this variant is an in-frame deletion, regardless of its SpliceAI maximum delta 0.068. Details ▾Hide ▴
Reasoning

The variant is an in-frame deletion, not a synonymous (silent) or intronic variant. The VCEP BP7 rule is limited to silent variants inside a potentially clinically important functional domain or intronic variants outside conserved donor/acceptor motif positions, with BP4 met. Neither BP7 applicability path covers this in-frame deletion. The SpliceAI maximum delta score of 0.068 cannot make BP7 applicable. No BP7 code is pre-assigned for this variant in the searched ENIGMA supplementary tables.

VCEP rule
Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
Evidence considered
  • Case normalization identifies NM_007294.4:c.1106_1108del as NP_009225.1:p.(Asp369del), an in-frame deletion.
  • ENIGMA Specifications v1.2, BP7 applies to silent variants inside a potentially clinically important functional domain if BP4 is met, and to intronic variants outside conserved donor or acceptor motif positions if BP4 is met; it does not include in-frame deletions.
  • Case SpliceAI result: maximum delta 0.068 (DS_DG 0.068), which is not a basis for extending BP7 beyond the variant types named by the VCEP.
  • Search of SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.1106_1108del, p.Asp369del, and p.D369del found no pre-assigned BP7 code for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

9 paper records listed. 1 cited in the classification.

Cited in the classification

  • Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
    Parsons MT et al. · 2019 Sep
    → BS4 · strong
    PMID 31131967 ↗

Other recorded publications

  • Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group.
    Anglian Breast Cancer Study Group · 2000
    The paper explicitly reports BRCA1 1224delGAT (D369del), corresponding to c.1106_1108del and p.(D369del), in one breast cancer patient diagnosed at age 53 without a family history of breast or ovarian cancer. It states that the deleted amino acid is conserved in murine Brca1 but lies outside any known functional domain, and that the functional significance was uncertain.
    Names this variant
    PMID 11044354 ↗
    Quoted passage
    The BRCA1 variant 1224delGAT (D369del) was found in a patient aged 53 at diagnosis who had no family history of breast or ovarian cancer and is reported on the BIC database. The deleted amino acid is conserved in murine Brca1 but does not lie within any known functional domain. As the functional significance of these variants is uncertain we have not included them in the analysis.

    Results, BRCA1 and BRCA2 mutation prevalence, paragraph describing in-frame deletions

  • Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
    Judkins T et al. · 2005
    This paper explicitly reports D369del (1225del3), corresponding to the queried p.(D369del), among variants observed in trans with the known deleterious BRCA1 mutation 5385insC; it reports occurrence 8-19 times in a 55,630-patient clinical-testing dataset, without a matched unaffected control comparison.
    Names this variant
    PMID 16267036 ↗
    Quoted passage
    D369del (1225del3) 5385insC D369del* (U)

    Table 4, heterozygous haplotypes; Table 2, Haplotype 2

  • Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.
    Chenevix-Trench G et al. · 2006
    No paper-specific finding is recorded.
    PMID 16489001 ↗
  • A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.
    Easton DF et al. · 2007
    The paper reports a broad multifactorial assessment of BRCA1/BRCA2 variants, but the exact c.1106_1108del/p.(D369del) variant is not mentioned and no variant-specific LR is available for PP4 or BP5.
    Does not name this variant
    PMID 17924331 ↗
    Quoted passage
    These “variants of unknown significance” (VUSs) are mainly missense mutations but also include a number of intronic variants and inframe deletions and insertions (IFDIs).

    Introduction, paragraph 1; Methods, “Evaluation of Heterogeneity by Variant Class”

  • High-throughput resequencing in the diagnosis of BRCA1/2 mutations using oligonucleotide resequencing microarrays.
    Schroeder C et al. · 2010
    No paper-specific finding is recorded.
    PMID 19941162 ↗
  • Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
    No paper-specific finding is recorded.
    PMID 20104584 ↗
  • A guide for functional analysis of BRCA1 variants of uncertain significance.
    Millot GA et al. · 2012
    No paper-specific finding is recorded.
    PMID 22753008 ↗
  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • 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 v4.1 156 / 1,614,042 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.068 Open source ↗
ClinVar 9 Likely benign · 3 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

This variant is present in gnomAD v4.1 (AF= 9.66518e-05; MAF= 0.00967%, 156/1614042 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000124572; MAF= 0.01246%, 147/1180044 alleles, homozygotes = 0); grpmax FAF= 0.00010792.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 5.17586e-05; MAF= 0.00518%, 13/251166 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000114531; MAF= 0.01145%, 13/113506 alleles, homozygotes = 0); grpmax FAF= 6.675e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010860121633362293, 2/18416 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 54130)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

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.