0%
BRCA1c.2927A>GLikely benign
Print report
Variant interpretation report

BRCA1 c.2927A>G, p.(Asn976Ser)

NM_007294.4:c.2927A>G NP_009225.1:p.(Asn976Ser) Missense · exon 10 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

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

In plain language

Gene-level background from the recorded interpretation.

About 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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at supporting: the variant is absent from the preferred non-cancer gnomAD exome and genome datasets required by the ENIGMA PM2 rule.

Benign criteria applied · 1
BP1Strong
BP1 · strong

Met, Strong: residue 976 is outside approved BRCA1 domains and SpliceAI max delta 0.004 is below the <=0.1 BP1 threshold.

Recorded classification: Likely benign

Likely Benign: BP1 (strong) outweighs PM2 (supporting) under ENIGMA's conflicting-evidence point system, yielding a net score of -3.

02The sources

Evidence at a glance

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

No screenshot for this evidence
REVEL score
0.396 recorded score

Recorded REVEL score: 0.396. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only 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.

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

This variant has previously been reported in somatic cancers (COSMIC; COSV58783414, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 6 not met · 10 not assessed · 10 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

PM3 cannot be assigned without a qualifying Fanconi-anemia phenotype and same-gene pathogenic/likely pathogenic co-occurrence with phase or phase-unknown information.

BP2 is not applicable because the governing ENIGMA VCEP specification explicitly prohibits its use except in the BS2 context.

Met · 2

PM2 SupportingMet at supporting: the variant is absent from the preferred non-cancer gnomAD exome and genome datasets required by the ENIGMA PM2 rule. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies PM2_Supporting for absence from gnomAD exome and genome datasets, preferring gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with adequate read depth and no failed quality-control filter. The case evidence reports this variant absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer, with no quality or depth failure reported. This supports PM2 at the VCEP-specified supporting strength. The variant was not found in the searched variant-level VCEP tables.

Rule
PM2_Supporting: absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, subject to read-depth and quality-control requirements.
Evidence considered
  • ENIGMA BRCA1 VCEP PM2 rule: absence from gnomAD exome and genome datasets supports PM2_Supporting, with preferred sources gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes; a single observation is not informative and quality-control failures exclude the evidence.
  • The case population data report the variant absent from gnomAD v2.1 non-cancer, gnomAD v3.1 non-cancer, gnomAD v2.1, and gnomAD v4.1, with no quality or depth failure reported.
Still missing
  • No variant-specific entry was found when searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP1 StrongMet, Strong: residue 976 is outside approved BRCA1 domains and SpliceAI max delta 0.004 is below the <=0.1 BP1 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification applies BP1_Strong to missense variants outside a potentially clinically important functional domain when no splicing is predicted (SpliceAI <=0.1). The variant is p.Asn976Ser at residue 976, outside the complete governing BRCA1 domain list (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857), and its SpliceAI maximum delta is 0.004, satisfying the <=0.1 requirement. BP1_Strong is met.

Rule
ENIGMA BP1_Strong: missense or qualifying exonic variant outside a potentially clinically important functional domain AND no predicted splicing (SpliceAI <=0.1).
Evidence considered
  • ENIGMA Specification v1.2 applies BP1_Strong to missense variants outside a potentially clinically important functional domain with no predicted splicing (SpliceAI <=0.1); missense prediction is not required for BP1.
  • BRCA1 approved critical or potentially critical domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 976 is outside every listed domain.
  • SpliceAI reports DS_AG 0.000, DS_AL 0.003, DS_DG 0.004, and DS_DL 0.000; the maximum delta is 0.004, below the VCEP BP1 cutoff of 0.1.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18spliceai ↗

Not met · 6 · evaluated, threshold not reached

PP3 Not met: REVEL 0.396 is below the 0.644 supporting PP3 threshold, and the ENIGMA BayesDel score -0.187387 is below 0.28. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2927A>G is a missense variant, so PP3/BP4 must use the missense protein-impact path and must not use SpliceAI as evidence for the amino-acid substitution. The governing ENIGMA BRCA1 v1.2 specification permits PP3 for a missense variant in a clinically important domain when BayesDel no-AF is at least 0.28; the case BayesDel score is -0.187387 and therefore does not meet that VCEP threshold. Using the supplied generic REVEL calibration as the applicable missense predictor, REVEL 0.396 is below the PP3 supporting threshold of 0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. No exact c.2927A>G, p.Asn976Ser, or p.N976S 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.

Rule
ENIGMA BRCA1 v1.2 PP3 missense protein-impact rule: BayesDel no-AF >=0.28; generic REVEL PP3 supporting threshold: >=0.644.
Evidence considered
  • The ENIGMA BRCA1 v1.2 missense protein-impact rule specifies PP3 when BayesDel no-AF is at least 0.28; this variant's BayesDel no-AF score is -0.187387.
  • The supplied ClinGen SVI REVEL calibration assigns PP3 supporting at REVEL >=0.644; this missense variant's REVEL score is 0.396, below that threshold (Pejaver et al. 2022, PMID:36413997).
  • Because the variant is missense, SpliceAI was not used to support or refute PP3; the missense protein-impact path is assessed without combining predictor paths.
Still missing
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelbayesdel
PP5 Not met: ClinVar reported zero expert-panel submissions for c.2927A>G, so the required exact-variant Pathogenic or Likely pathogenic trigger is absent. Details ▾Hide ▴
Reasoning

PP5 is applied here only if an exact-variant ClinVar Expert Panel classification reports Pathogenic or Likely pathogenic. The reviewed ClinVar result for NM_007294.4:c.2927A>G reports no result, with no classification, no review status, no submissions, and zero expert-panel submissions. Therefore the required exact-variant Expert Panel trigger is absent; ordinary submissions, aggregate labels, and non-expert assertions cannot trigger PP5. The BRCA1 VCEP specification itself says PP5 is not for use, but that does not create a PP5 assertion in the absence of the separately required exact-variant Expert Panel evidence.

Rule
Apply at Supporting strength only for an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • The reviewed ClinVar result for NM_007294.4:c.2927A>G reported no result, no classification, no review status, no submissions, and zero expert-panel submissions.
  • PP5 was restricted to an exact-variant ClinVar Expert Panel Pathogenic/Likely pathogenic classification; no such trigger exists for this variant.
  • The ENIGMA V1.2 specification states that PP5 is not for use by this VCEP.
Still missing
  • No exact-variant ClinVar Expert Panel Pathogenic or Likely pathogenic classification was found.
  • The reviewed ClinVar record reported no result and zero expert-panel submissions.
Sources
cspec ↗
BA1 Not met: the variant is absent from the governing non-cancer gnomAD datasets, so its filter allele frequency does not exceed the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies BA1 when the maximum filter allele frequency exceeds 0.001 (0.1%) in non-founder populations using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The case evidence reports this variant as absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer, so no allele frequency exceeds the BA1 threshold. The variant was not found in the searched variant-level VCEP tables.

Rule
Filter allele frequency >0.001 in gnomAD v2.1 non-cancer exome and/or gnomAD v3.1 non-cancer genome non-founder populations.
Evidence considered
  • ENIGMA BRCA1 VCEP BA1 rule: apply stand-alone benign evidence when filter allele frequency is above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
  • The case population data report the variant absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, and gnomAD v3.1 non-cancer; therefore no qualifying allele frequency is available above 0.001.
Still missing
  • No variant-specific entry was found when searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: the variant is absent from the preferred non-cancer gnomAD datasets, so no filter allele frequency exceeds the ENIGMA BS1 threshold of 0.0001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies BS1 when the maximum filter allele frequency exceeds 0.0001 (0.01%), with the same preferred non-cancer gnomAD v2.1 exome and gnomAD v3.1 genome sources and read-depth and quality controls. The case evidence reports the variant absent from both preferred non-cancer datasets and the all-comers gnomAD datasets, so no qualifying frequency exceeds 0.0001. The variant was not found in the searched variant-level VCEP tables.

Rule
Filter allele frequency >0.0001 in gnomAD v2.1 non-cancer exome and/or gnomAD v3.1 non-cancer genome non-founder populations.
Evidence considered
  • ENIGMA BRCA1 VCEP BS1 rule: apply strong benign evidence above 0.0001 using maximum filter allele frequency in preferred non-cancer gnomAD v2.1 exomes and/or gnomAD v3.1 genomes.
  • The case population data report the variant absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, as well as gnomAD v2.1 and gnomAD v4.1; therefore no qualifying frequency is available above 0.0001.
Still missing
  • No variant-specific entry was found when searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 Not met: REVEL 0.396 exceeds the <=0.29 supporting BP4 threshold and remains in the gray zone for benign protein impact. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2927A>G is a missense variant, so BP4 must use the missense protein-impact path and must not use its low SpliceAI score as benign evidence for the amino-acid substitution. The governing ENIGMA BRCA1 v1.2 rule requires BayesDel no-AF at most 0.15 together with SpliceAI at most 0.1 for its missense BP4 application; although BayesDel is -0.187387, the missense-path rule here does not substitute or combine splice prediction for protein-impact evidence. The supplied generic REVEL calibration gives BP4 supporting only at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997); REVEL is 0.396, in the gray zone, so BP4 is not met. No exact c.2927A>G, p.Asn976Ser, or p.N976S 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.

Rule
ENIGMA BRCA1 v1.2 BP4 missense rule: BayesDel no-AF <=0.15 and SpliceAI <=0.1; generic REVEL BP4 supporting threshold: <=0.29.
Evidence considered
  • The ENIGMA BRCA1 v1.2 missense BP4 rule requires BayesDel no-AF <=0.15 and SpliceAI <=0.1; BayesDel is -0.187387, but the missense-path adjudication does not use SpliceAI as protein-impact evidence.
  • The supplied ClinGen SVI REVEL calibration assigns BP4 supporting at REVEL <=0.29; this variant's REVEL score is 0.396, which is above the threshold and therefore gray-zone (Pejaver et al. 2022, PMID:36413997).
  • A gray-zone REVEL result does not permit substitution of the SpliceAI score for BP4.
Still missing
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelbayesdel
BP6 Not met: ClinVar reported zero expert-panel submissions for c.2927A>G, so the required exact-variant Benign or Likely benign trigger is absent. Details ▾Hide ▴
Reasoning

BP6 is applied here only if an exact-variant ClinVar Expert Panel classification reports Benign or Likely benign. The reviewed ClinVar result for NM_007294.4:c.2927A>G reports no result, with no classification, no review status, no submissions, and zero expert-panel submissions. Therefore the required exact-variant Expert Panel trigger is absent; ordinary submissions, aggregate labels, and non-expert assertions cannot trigger BP6. The BRCA1 VCEP specification itself says BP6 is not for use, but that does not create a BP6 assertion in the absence of the separately required exact-variant Expert Panel evidence.

Rule
Apply at Supporting strength only for an exact-variant ClinVar Expert Panel classification of Benign or Likely benign; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • The reviewed ClinVar result for NM_007294.4:c.2927A>G reported no result, no classification, no review status, no submissions, and zero expert-panel submissions.
  • BP6 was restricted to an exact-variant ClinVar Expert Panel Benign/Likely benign classification; no such trigger exists for this variant.
  • The ENIGMA V1.2 specification states that BP6 is not for use by this VCEP.
Still missing
  • No exact-variant ClinVar Expert Panel Benign or Likely benign classification was found.
  • The reviewed ClinVar record reported no result and zero expert-panel submissions.
Sources
cspec ↗

Not assessed · 10 · no assessment recorded

PS1 Not assessed: SpliceAI max delta is 0.004, but no qualifying previously pathogenic alternate producing p.Asn976Ser was identified. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification allows PS1 for a missense substitution producing the same amino-acid change as a previously established pathogenic variant, provided the reference variant acts through protein change and has no confirmed or predicted splice impact (SpliceAI <=0.1). This variant is missense, with SpliceAI maximum delta 0.004, but no qualifying previously pathogenic alternate nucleotide change producing p.Asn976Ser/p.N976S was identified in the collected evidence. The four governing searchable VCEP files had no entry for c.2927A>G, p.Asn976Ser, or p.N976S, and the case comparator search contained zero candidates; therefore PS1 cannot be established from the available evidence.

Rule
ENIGMA PS1: same amino-acid change as a previously established pathogenic variant; for a missense protein-change application, no confirmed or predicted splice impact (SpliceAI <=0.1).
Evidence considered
  • ENIGMA BRCA1/2 Specification v1.2 states that PS1 applies to a missense substitution with the same amino-acid change as a previously established pathogenic variant; for protein-change application, the reference variant must have no confirmed or predicted mRNA splicing effect (SpliceAI <=0.1).
  • The case variant is NM_007294.4:c.2927A>G, p.Asn976Ser/p.N976S, and SpliceAI maximum delta is 0.004.
  • ClinVar returned no variant-specific record, and the collected comparator search contained zero same-residue candidates; this does not establish that no such variant exists outside the reviewed sources.
Still missing
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No qualifying pathogenic same-amino-acid comparator variant was present in pm5_candidates.json or the case evidence bundle.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18clinvar ↗spliceai ↗pm5_candidates
PS3 Not assessed: no variant-specific calibrated damaging functional assay result or ENIGMA PS3 assignment was found for c.2927A>G. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 specification reserves PS3 for well-established protein-function assays or assays combining mRNA and protein data, with strength assigned from calibrated results in Specifications Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt (including ST4), Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt found no entry for c.2927A>G, p.Asn976Ser, or p.N976S. The case evidence contains no variant-specific functional assay result or extracted functional paper finding, so a calibrated damaging assay result and PS3 strength cannot be established.

Rule
Apply PS3 only for well-established in vitro or in vivo functional studies supportive of a damaging effect when the assay measures protein function or combined mRNA and protein effects; use the ENIGMA calibrated Table 9 recommendation when an applicable variant entry exists.
Evidence considered
  • ENIGMA BRCA1 V1.2 specifies PS3 for well-established in vitro or in vivo studies showing a damaging effect measured through protein function or combined mRNA and protein effects, with calibrated recommendations in Table 9.
  • The exact variant notations c.2927A>G, p.Asn976Ser, and p.N976S were searched in each governing functional VCEP text file; no variant-level entry was found.
  • The case normalization identifies NM_007294.4:c.2927A>G as the missense change NP_009225.1:p.(Asn976Ser), but the case evidence provides no variant-specific functional assay result.
Still missing
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in HUMU-40-1557-s001.xlsx.txt.
  • No variant-specific functional assay finding is available in the case paper_extracts.json material.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
PS4 Not assessed: no variant-specific PS4 case-control odds ratio, confidence interval, or p-value was available for comparison with OR >=4 and p-value <=0.05. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specifies PS4 Strong when a matched case-control study has p-value <=0.05, OR >=4, and a lower confidence interval that excludes 2.0. No variant-specific case-control dataset, odds ratio, confidence interval, or p-value for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S) is present in the reviewed case evidence. The variant was searched under all three supplied notations in the governing full-text VCEP directory, with no entry found in Specifications_V1.2_2024-11-18.docx.txt, PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt, or PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt; those files are not PS4 case-control datasets. PS4 cannot therefore be assigned or excluded from a quantitative comparison.

Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
Evidence considered
  • ENIGMA BRCA1 V1.2 Table 1 states: 'Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).'
  • The reviewed case evidence contains no variant-specific PS4 case-control metric for NM_007294.4:c.2927A>G.
  • The variant was searched as c.2927A>G, p.Asn976Ser, and p.N976S in the governing VCEP full-text files; no matching entry was found.
Still missing
  • No variant-specific ethnicity- and country-matched case-control counts, odds ratio, confidence interval, or p-value were found.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt; this file is a PP4/BP5 clinical-history component, not a PS4 case-control dataset.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
Sources
cspec ↗
PM3 Not assessed: no Fanconi-anemia phenotype, second BRCA1 pathogenic allele, or phase observation is documented for PM3 point assignment. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP specification restricts PM3 to patients with a phenotype consistent with BRCA1-related Fanconi anemia and a co-occurrent pathogenic or likely pathogenic variant in BRCA1, with strength determined from Table 6 points: 1 point for phase unknown and 2 points for a documented in-trans pathogenic/likely pathogenic variant or homozygosity. The available case materials provide no affected-proband Fanconi-anemia phenotype, second BRCA1 pathogenic/likely pathogenic allele, phase, or inheritance observation for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S). The governing full-text specification was searched for c.2927A>G, p.Asn976Ser, and p.N976S without a variant-specific entry; this is a missing case observation, not evidence that the allelic observation is absent.

Rule
ENIGMA BRCA1/2 VCEP PM3_VariableWeight: apply only with a phenotype consistent with BRCA1/2-related Fanconi anemia and co-occurrent pathogenic/likely pathogenic variants in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
  • The ENIGMA BRCA1/2 VCEP specification defines PM3 only for a BRCA1- or BRCA2-related Fanconi-anemia phenotype with a co-occurrent pathogenic or likely pathogenic variant in the same gene.
  • ENIGMA Table 6 assigns 2 points for a pathogenic/likely pathogenic variant in trans or homozygosity and 1 point when phase is unknown; no qualifying proband observation or point-bearing allele is present in the reviewed case materials.
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.2927A>G, p.Asn976Ser, and p.N976S; no variant-specific entry was found.
Still missing
  • No affected-proband Fanconi-anemia phenotype or qualifying chromosome-breakage/clinical features are documented.
  • No co-occurrent BRCA1 pathogenic or likely pathogenic variant is documented.
  • No phase or inheritance information is documented to establish trans, cis, homozygous, or phase-unknown status.
  • No variant-specific entry was found after searching Specifications_V1.2_2024-11-18.docx.txt for c.2927A>G, p.Asn976Ser, and p.N976S.
Sources
cspec ↗
PP1 Not assessed: no variant-specific affected-family genotypes, meioses, or quantitative co-segregation LR were provided to compare with the PP1 threshold of 2.08:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 requires quantitative co-segregation evidence from multiple affected family members and assigns PP1 variable weight by Bayes score: supporting at LR ≥2.08:1, moderate at LR ≥4.3:1, strong at LR ≥18.7:1, and very strong at LR ≥350:1. The case materials provide no variant-specific pedigree, affected-relative genotypes, meioses, parental testing, or quantitative co-segregation likelihood ratio for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S), so PP1 cannot be assessed.

Rule
PP1 variable weight by quantitative co-segregation Bayes score: supporting LR ≥2.08:1; moderate LR ≥4.3:1; strong LR ≥18.7:1; very strong LR ≥350:1.
Evidence considered
  • ENIGMA BRCA1/2 Specification v1.2, PP1: use quantitative co-segregation with multiple affected family members and apply variable weight by Bayes score, starting at LR ≥2.08:1 for supporting evidence.
  • The case-evidence bundle contains no variant-specific segregation, parental-testing, affected-relative genotype, meiosis, or co-segregation-LR result for this variant.
  • The required VCEP full-text searches found no entry for c.2927A>G, p.Asn976Ser, or p.N976S in Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt.
Still missing
  • No variant-specific pedigree or affected-relative genotype data in the case bundle for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S).
  • No quantitative co-segregation likelihood ratio or meiosis count is available.
  • The variant was not found in Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt under c.2927A>G, p.Asn976Ser, or p.N976S; these files therefore provide no variant-specific segregation assignment.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP4 Not assessed: no variant-specific combined clinical likelihood ratio was available for comparison with the PP4 Supporting threshold LR >=2.08. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP restricts PP4 to a clinically calibrated combined likelihood ratio toward pathogenicity, not phenotype prevalence alone. The governing thresholds are PP4 Supporting LR >=2.08, Moderate LR >=4.3, Strong LR >=18.7, and Very Strong LR >=350; combined LR 1.00 to <2.08 is not informative. The case contains no exact BRCA1 c.2927A>G row in the gene-specific Li et al. clinical-history LR table and no variant-specific combined clinical LR from family history, segregation, co-occurrence, tumour pathology, or case-control data. Easton et al. and Li et al. provide methodology and threshold context but do not provide an exact-variant PP4 result here.

Rule
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. Combined LR 1.00 to <2.08 is not informative.
Evidence considered
  • ENIGMA BRCA1 V1.2 specifies PP4 only for combined multifactorial clinical LR and gives Supporting LR >=2.08, Moderate LR >=4.3, Strong LR >=18.7, and Very Strong LR >=350.
  • The gene-specific Li et al. clinical-history LR table was searched for exact BRCA1 c.2927A>G and contains no matching row.
  • Li et al. 2020 and Easton et al. 2007 were reviewed as methodology/context sources; neither supplies an exact-variant PP4 LR in this case.
Still missing
  • No exact Gene=BRCA1 and HGVS_Nucleotide=c.2927A>G row was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
  • No variant-specific combined LR integrating clinical-history, segregation, co-occurrence, tumour pathology, or case-control data was found.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
Sources
cspec ↗PMID:31853058 ↗PMID:17924331 ↗
BS2 Not assessed: no qualifying healthy-adult clinical observation or ENIGMA BS2 point data are available for this variant, and gnomAD frequency data cannot substitute for BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP applies BS2 using scored observations in phenotyped clinical or research individuals meeting its healthy-adult, genotype/phase, age, cancer-onset, and absence-of-Fanconi-Anemia stipulations; gnomAD homozygote observations are explicitly excluded from BS2 because they are captured by frequency codes. The consolidated case evidence contains no qualifying healthy-adult proband observations, homozygote or phase data, age/follow-up data, or Fanconi-Anemia assessment for this variant. Therefore BS2 cannot be assigned from the available evidence.

Rule
Assign BS2 from ENIGMA Table 8 point totals: strong at >=4 points, moderate at 2 points, supporting at 1 point; do not use gnomAD frequency observations for BS2.
Evidence considered
  • ENIGMA BRCA1 VCEP BS2 requires scored observations in phenotyped individuals and states that homozygotes observed only in gnomAD are not used for BS2 because they are captured by BA1 or BS1.
  • The case evidence provides no qualifying healthy-adult clinical/research observation, homozygote or phase information, age/follow-up data, cancer-onset information, or Fanconi-Anemia phenotype assessment.
Still missing
  • No qualifying clinical or research-cohort BS2 observation with genotype/phase, age or follow-up, cancer-onset, and Fanconi-Anemia phenotype information was found.
  • No variant-specific entry was found when searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 Not assessed: no variant-specific calibrated benign functional assay result or ENIGMA BS3 assignment was found for c.2927A>G. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 specification reserves BS3 for well-established protein-function assays or assays combining mRNA and protein data that show no damaging effect, with strength assigned from calibrated results in Specifications Table 9. Searches of Specifications_Table9_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt (including ST4), Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt found no entry for c.2927A>G, p.Asn976Ser, or p.N976S. The case evidence contains no variant-specific functional assay result or extracted functional paper finding, so a calibrated benign assay result and BS3 strength cannot be established.

Rule
Apply BS3 only for well-established in vitro or in vivo functional studies showing no damaging effect when the assay measures protein function or combined mRNA and protein effects; use the ENIGMA calibrated Table 9 recommendation when an applicable variant entry exists.
Evidence considered
  • ENIGMA BRCA1 V1.2 specifies BS3 for well-established in vitro or in vivo studies showing no damaging effect measured through protein function or combined mRNA and protein effects, with calibrated recommendations in Table 9.
  • The exact variant notations c.2927A>G, p.Asn976Ser, and p.N976S were searched in each governing functional VCEP text file; no variant-level entry was found.
  • The case normalization identifies NM_007294.4:c.2927A>G as the missense change NP_009225.1:p.(Asn976Ser), but the case evidence provides no variant-specific functional assay result.
Still missing
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including ST4.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S in HUMU-40-1557-s001.xlsx.txt.
  • No variant-specific functional assay finding is available in the case paper_extracts.json material.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
BS4 Not assessed: no variant-specific non-segregating affected relatives, meioses, or quantitative LR were provided to compare with the BS4 threshold of ≤0.48:1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 requires quantitative evidence of lack of segregation in affected family members and assigns BS4 variable weight by Bayes score: supporting at LR ≤0.48 and >0.23:1, moderate at LR ≤0.23:1, strong at LR ≤0.05:1, and very strong at LR ≤0.00285:1. The case materials provide no variant-specific non-segregation observations, affected-relative genotypes, meioses, or quantitative co-segregation likelihood ratio for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S), so BS4 cannot be assessed.

Rule
BS4 variable weight by quantitative lack-of-segregation Bayes score: supporting LR ≤0.48 and >0.23:1; moderate LR ≤0.23:1; strong LR ≤0.05:1; very strong LR ≤0.00285:1.
Evidence considered
  • ENIGMA BRCA1/2 Specification v1.2, BS4: use quantitative lack-of-segregation evidence in affected family members and apply variable weight by Bayes score, starting at LR ≤0.48 and >0.23:1 for supporting evidence.
  • The case-evidence bundle contains no variant-specific non-segregation, parental-testing, affected-relative genotype, meiosis, or co-segregation-LR result for this variant.
  • The required VCEP full-text searches found no entry for c.2927A>G, p.Asn976Ser, or p.N976S in Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt.
Still missing
  • No variant-specific non-segregation observations or affected-relative genotype data in the case bundle for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S).
  • No quantitative co-segregation likelihood ratio or meiosis count is available.
  • The variant was not found in Specifications_V1.2_2024-11-18.docx.txt or HUMU-40-1557-s001.xlsx.txt under c.2927A>G, p.Asn976Ser, or p.N976S; these files therefore provide no variant-specific segregation assignment.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP5 Not assessed: no variant-specific combined LR was available to test the BP5 Supporting inequality LR <=0.48 and >0.23. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP restricts BP5 to a clinically calibrated combined likelihood ratio against pathogenicity. The governing comparison operators are BP5 Supporting LR <=0.48 and >0.23, Moderate LR <=0.23 and >0.05, Strong LR <=0.05 and >0.00285, and Very Strong LR <=0.00285; combined LR >0.48 to 1.00 is not informative. No exact-variant clinical-history LR or combined multifactorial LR for NM_007294.4:c.2927A>G (p.Asn976Ser/p.N976S) is available, so no substituted inequality can be evaluated and no BP5 strength can be assigned.

Rule
Use ONLY to capture combined LR against pathogenicity based on multifactorial likelihood clinical data: BP5 Supporting LR <=0.48 and >0.23:1; BP5_Moderate LR <=0.23 and >0.05:1; BP5_Strong LR <=0.05 and >0.00285:1; BP5_Very Strong LR <=0.00285:1. Combined LR >0.48 to 1.00 is not informative.
Evidence considered
  • ENIGMA BRCA1 V1.2 states BP5 Supporting LR <=0.48 and >0.23, Moderate LR <=0.23 and >0.05, Strong LR <=0.05 and >0.00285, and Very Strong LR <=0.00285.
  • The BP5 Supporting comparison is explicitly LR <=0.48 and >0.23; no value was available to substitute into that inequality.
  • The gene-specific Li et al. clinical-history LR table was searched for exact BRCA1 c.2927A>G and contains no matching row; Easton and Li provide methodology/context only.
Still missing
  • No exact Gene=BRCA1 and HGVS_Nucleotide=c.2927A>G row was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
  • No variant-specific combined LR against pathogenicity from clinical-history, segregation, co-occurrence, tumour pathology, or case-control data was found.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
Sources
cspec ↗PMID:31853058 ↗PMID:17924331 ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.2927A>G produces missense p.Asn976Ser with no premature termination, unchanged protein length, and no PVS1 null-variant consequence. Details ▾Hide ▴
Reasoning

Not applicable: NM_007294.4:c.2927A>G is a validated exonic missense substitution, NP_009225.1:p.(Asn976Ser) (p.N976S), in exon 10, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. ENIGMA BRCA1 v1.2 defines PVS1 for null variants and directs exon-level weighting through Table 4; the governing Table 4 has no entry for c.2927A>G, p.Asn976Ser, or p.N976S. The observed protein length is unchanged and there is no NMD-triggering premature termination codon. SpliceAI max delta is 0.004, but this missense consequence does not enter the PVS1 splice/null pathway.

Rule
ENIGMA BRCA1/2 v1.2 PVS1 applies to null variants; missense substitutions are not eligible for PVS1.
Evidence considered
  • VariantValidator confirms the governing transcript NM_007294.4 and protein consequence NP_009225.1:p.(Asn976Ser), with the variant located in BRCA1 exon 10.
  • ENIGMA BRCA1/2 v1.2 limits PVS1 to null variants and requires Table 4/Appendix D exon-specific application; this missense substitution is outside that pathway.
  • SpliceAI reports max delta 0.004, providing no splice-loss consequence that would convert this missense substitution into a PVS1 splice assessment.
Still missing
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PS2 VCEPNot applicable: ENIGMA v1.2 explicitly prohibits PS2 because de novo observations lack calibrated predictive value for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 explicitly says not to use PS2 because BRCA1/2-related cancers occur relatively commonly and there is no calibration of the predictive capacity of de novo observations. The governing specification also defines PS2 as de novo occurrence with confirmed paternity, disease in the patient, and no family history.

VCEP rule
Do not use PS2 for BRCA1/2-related cancers; no calibration exists for the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA1/2 Specification v1.2, PS2: de novo with confirmed paternity is listed as Do not use because BRCA1/2-related cancers are relatively common and de novo predictive capacity is not calibrated.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM1 VCEPNot applicable: ENIGMA marks PM1 N/A, and residue 976 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 specification explicitly marks PM1 as not applicable and states that it is considered within the calibrated bioinformatic framework rather than applied as an independent criterion. The authoritative vcep_materials.json domain_tables object contains no BRCA1 entry. Using the complete domain list stated in the governing specification, BRCA1 critical or potentially critical domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 976 lies in none of them. PM1 is therefore not applicable under this VCEP framework.

VCEP rule
ENIGMA PM1: not applicable; evaluate domain-related information through BP1, BP4, and PP3 rather than applying PM1 independently.
Evidence considered
  • ENIGMA Specification v1.2 Table 1 marks PM1 as 'Do not use' and states that domain information is considered through the calibrated bioinformatic criteria.
  • The governing BRCA1 domain definitions are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Asn976 is outside all three.
  • vcep_materials.json has an empty domain_tables object, so no gene-specific extracted domain table supersedes the governing specification domain definitions.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM4 VCEPNot applicable: PM4 is not used by ENIGMA, and p.Asn976Ser is a missense substitution with no in-frame length change or stop-loss event. Details ▾Hide ▴
Reasoning

Not applicable: ENIGMA BRCA1/2 v1.2 explicitly states that PM4 is not used and is instead considered within the bioinformatic analysis framework. This variant is a missense substitution, p.Asn976Ser, with no in-frame deletion/insertion, stop-loss event, or protein-length change. The predicted protein remains full length at 1863 amino acids; therefore the PM4 protein-length-change definition is not met.

VCEP rule
ENIGMA BRCA1/2 v1.2: PM4 do not use; protein-length-change evidence is captured through the bioinformatic framework.
Evidence considered
  • ENIGMA Table 1 states that PM4 is not used for BRCA1/2 and is considered as a component of bioinformatic analysis.
  • VariantValidator predicts p.(Asn976Ser), a single-residue missense substitution, with no protein truncation, stop-loss, insertion, or deletion.
  • The normalized full-length BRCA1 protein remains 1863 amino acids, so no protein-length change is present.
Still missing
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM5 N/ANot applicable: ENIGMA repurposes PM5 for PVS1-eligible PTC variants, whereas c.2927A>G is a missense substitution. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification explicitly marks classic missense PM5 as not applicable because some residues can harbor both pathogenic and non-pathogenic substitutions. It repurposes PM5 only as PM5 (PTC) for genomic protein-termination variants that meet PVS1, with exon-specific weights. This variant is a missense substitution, not a PTC or truncating variant, and no VCEP table entry for c.2927A>G, p.Asn976Ser, or p.N976S was found.

Rule
ENIGMA PM5: classic missense PM5 not applicable; PM5 (PTC) is limited to genomic protein-termination variants meeting PVS1.
Evidence considered
  • ENIGMA Specification v1.2 states that classic missense PM5 is not applicable and evaluates it through BP1, BP4, and PP3; its PM5 (PTC) repurposing is limited to genomic PTC variants annotated with PVS1.
  • The case variant is classified as missense, p.Asn976Ser/p.N976S, not a PTC or truncating variant.
  • The VCEP PM5 candidate artifact contains zero same-residue candidates and explicitly identifies the gene-specific PM5 mode as PTC/truncating logic.
Still missing
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.2927A>G, p.Asn976Ser, or p.N976S was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18pm5_candidates
PM6 VCEPNot applicable: ENIGMA v1.2 explicitly prohibits PM6 because de novo observations lack calibrated predictive value for relatively common BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 explicitly says not to use PM6 because BRCA1/2-related cancers occur relatively commonly and there is no calibration of the predictive capacity of de novo observations. PM6 is therefore excluded even if de novo status were reported without confirmed paternity and maternity.

VCEP rule
Do not use PM6 for BRCA1/2-related cancers; no calibration exists for the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA1/2 Specification v1.2, PM6: confirmed de novo without confirmation of paternity and maternity is listed as Do not use because BRCA1/2-related cancers are relatively common and de novo predictive capacity is not calibrated.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP2 VCEPNot applicable: ENIGMA excludes PP2 because missense variants are not a common pathogenicity mechanism for BRCA1. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 specification explicitly marks PP2 as not applicable because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2. The variant is missense, but the gene-specific VCEP rule excludes PP2 regardless of the individual residue or prediction scores.

VCEP rule
ENIGMA PP2: do not use for BRCA1/2 because missense variants are not a common pathogenicity mechanism.
Evidence considered
  • ENIGMA Specification v1.2 Table 1 marks PP2 as 'Do not use' and gives the reason that missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP2 VCEPNot applicable: the ENIGMA BRCA1/2 specification explicitly says BP2 is not used and limits it to the BS2 context. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 VCEP specification states that BP2 is not to be used and is applied only in the context of BS2. Therefore BP2 is not applicable to this BRCA1 variant under the governing framework, regardless of whether a cis or trans co-observation is available.

VCEP rule
ENIGMA BRCA1/2 VCEP BP2: Do not use; applied only in the context of BS2.
Evidence considered
  • The ENIGMA BRCA1/2 VCEP specification lists BP2 as 'Do not use' and states that it is applied only in the context of BS2.
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 is not used by ENIGMA, and this variant is a missense substitution rather than an in-frame insertion or deletion in a repeat region. Details ▾Hide ▴
Reasoning

Not applicable: ENIGMA BRCA1/2 v1.2 explicitly states that BP3 is not used and is captured by bioinformatic tool prediction and domain analysis. BP3 concerns in-frame deletions or insertions in a repetitive region without known function; this variant is neither an insertion nor a deletion, and it does not alter protein length. Therefore repeat-region context does not make BP3 applicable.

VCEP rule
ENIGMA BRCA1/2 v1.2: BP3 do not use; in-frame insertion/deletion repeat-region evidence is captured by bioinformatic prediction and domain analysis.
Evidence considered
  • ENIGMA Table 1 states that BP3 is not used and is captured by bioinformatic prediction and domain analysis.
  • The normalized consequence is p.(Asn976Ser), a missense substitution; no in-frame insertion or deletion and no repeat-region protein-length change are present.
Still missing
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2927A>G, p.Asn976Ser, or p.N976S entry found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP7 N/ANot applicable: c.2927A>G is missense, p.Asn976Ser, whereas BP7 is restricted to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_007294.4:c.2927A>G is a missense variant, producing NP_009225.1:p.(Asn976Ser), so BP7 is not applicable regardless of the available predictor scores or the absence of an exact variant entry in the governing VCEP files.

Rule
BP7 is applicable only to synonymous variants under the ENIGMA BRCA1 v1.2 specification.
Evidence considered
  • The case normalization identifies c.2927A>G as the missense substitution p.(Asn976Ser).
  • The ENIGMA BRCA1 v1.2 BP7 rule is restricted to silent/synonymous variants, so no BP7 predictor assessment is permitted for this variant.
Sources
cspec ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.2927A>G
Protein (HGVS p.)
NP_009225.1:p.(Asn976Ser)
GRCh38
chr17:43092604 T>C
GRCh37
chr17:41244621 T>C
Location and type
Exon 10 · missense
ClinVar
3625785, 3373180, 3226132, 3069955, 2833962, 629195, 233238, 232792
COSMIC
COSV58783414

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

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -465 bp
0.003
SpliceAI acceptor gainat +300 bp
0.000
SpliceAI donor lossat -3 bp
0.000
SpliceAI donor gainat -53 bp
0.004
Pangolin splice lossmagnitude shown
-0.006
Pangolin splice gain
0.002

Other predictors

REVEL
0.396
BayesDel
-0.187

How the predictions were used

PP3 Not met: REVEL 0.396 is below the 0.644 supporting PP3 threshold, and the ENIGMA BayesDel score -0.187387 is below 0.28. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2927A>G is a missense variant, so PP3/BP4 must use the missense protein-impact path and must not use SpliceAI as evidence for the amino-acid substitution. The governing ENIGMA BRCA1 v1.2 specification permits PP3 for a missense variant in a clinically important domain when BayesDel no-AF is at least 0.28; the case BayesDel score is -0.187387 and therefore does not meet that VCEP threshold. Using the supplied generic REVEL calibration as the applicable missense predictor, REVEL 0.396 is below the PP3 supporting threshold of 0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. No exact c.2927A>G, p.Asn976Ser, or p.N976S 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.

Rule
ENIGMA BRCA1 v1.2 PP3 missense protein-impact rule: BayesDel no-AF >=0.28; generic REVEL PP3 supporting threshold: >=0.644.
Evidence considered
  • The ENIGMA BRCA1 v1.2 missense protein-impact rule specifies PP3 when BayesDel no-AF is at least 0.28; this variant's BayesDel no-AF score is -0.187387.
  • The supplied ClinGen SVI REVEL calibration assigns PP3 supporting at REVEL >=0.644; this missense variant's REVEL score is 0.396, below that threshold (Pejaver et al. 2022, PMID:36413997).
  • Because the variant is missense, SpliceAI was not used to support or refute PP3; the missense protein-impact path is assessed without combining predictor paths.
Still missing
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelbayesdel
BP4 Not met: REVEL 0.396 exceeds the <=0.29 supporting BP4 threshold and remains in the gray zone for benign protein impact. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2927A>G is a missense variant, so BP4 must use the missense protein-impact path and must not use its low SpliceAI score as benign evidence for the amino-acid substitution. The governing ENIGMA BRCA1 v1.2 rule requires BayesDel no-AF at most 0.15 together with SpliceAI at most 0.1 for its missense BP4 application; although BayesDel is -0.187387, the missense-path rule here does not substitute or combine splice prediction for protein-impact evidence. The supplied generic REVEL calibration gives BP4 supporting only at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997); REVEL is 0.396, in the gray zone, so BP4 is not met. No exact c.2927A>G, p.Asn976Ser, or p.N976S 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.

Rule
ENIGMA BRCA1 v1.2 BP4 missense rule: BayesDel no-AF <=0.15 and SpliceAI <=0.1; generic REVEL BP4 supporting threshold: <=0.29.
Evidence considered
  • The ENIGMA BRCA1 v1.2 missense BP4 rule requires BayesDel no-AF <=0.15 and SpliceAI <=0.1; BayesDel is -0.187387, but the missense-path adjudication does not use SpliceAI as protein-impact evidence.
  • The supplied ClinGen SVI REVEL calibration assigns BP4 supporting at REVEL <=0.29; this variant's REVEL score is 0.396, which is above the threshold and therefore gray-zone (Pejaver et al. 2022, PMID:36413997).
  • A gray-zone REVEL result does not permit substitution of the SpliceAI score for BP4.
Still missing
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2927A>G, p.Asn976Ser, or p.N976S entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelbayesdel
BP7 N/ANot applicable: c.2927A>G is missense, p.Asn976Ser, whereas BP7 is restricted to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_007294.4:c.2927A>G is a missense variant, producing NP_009225.1:p.(Asn976Ser), so BP7 is not applicable regardless of the available predictor scores or the absence of an exact variant entry in the governing VCEP files.

Rule
BP7 is applicable only to synonymous variants under the ENIGMA BRCA1 v1.2 specification.
Evidence considered
  • The case normalization identifies c.2927A>G as the missense substitution p.(Asn976Ser).
  • The ENIGMA BRCA1 v1.2 BP7 rule is restricted to silent/synonymous variants, so no BP7 predictor assessment is permitted for this variant.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.396. BayesDel score = -0.187387.

5 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

  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    This paper does not mention BRCA1 c.2927A>G or NP_009225.1:p.(N976S); it discusses BRCA1 generally as a high-penetrance breast-cancer susceptibility gene.
    Does not name this variant
    PMID 18163131 ↗
    Quoted passage
    Disease-causing variants in BRCA1 and BRCA2 confer a high risk of breast cancer, approximately 10- to 20-fold relative risk.

    Rare high-penetrance breast cancer susceptibility genes, p. 17

  • American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
    Robson ME et al. · 2010
    This paper does not mention BRCA1 c.2927A>G or NP_009225.1:p.(N976S); it provides general BRCA1 risk and clinical utility context.
    Does not name this variant
    PMID 20065170 ↗
    Quoted passage
    BRCA1 Breast cancer 1/166 to 1/1,000; 1/82 (AJ) 32 (age 40-49 years) Mammography, MRI screening, risk-reducing surgery

    Table 1, Examples of Genes With Mutations and Variants Associated With Increased Risk of Cancer

  • NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
    This paper does not explicitly mention BRCA1 c.2927A>G or p.N976S; it summarizes general BRCA1 cancer-risk and DNA-repair biology.
    Does not name this variant
    PMID 23188549 ↗
    Quoted passage
    BRCA1 and BRCA2 are tumor suppressor genes. Their protein products are involved in the cellular response to DNA damage and double-stranded DNA repair.

    Clinical Features

  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    This paper does not report data specific to BRCA1 c.2927A>G or p.N976S; it is an ACMG policy statement on secondary findings.
    Does not name this variant
    PMID 25356965 ↗
    Quoted passage
    At the time of testing, the patient should be made aware that, regardless of the specific indication for testing, laboratories will routinely analyze the sequence of a set of genes deemed to be highly medically actionable.

    ACMG policy recommendations, page 2

  • Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
    This paper does not mention BRCA1 c.2927A>G or p.N976S; it lists BRCA1 as a hereditary breast and ovarian cancer gene for secondary-finding return.
    Does not name this variant
    PMID 27854360 ↗
    Quoted passage
    Hereditary breast and ovarian cancer ... BRCA1 ... AD ... KP and EP

    Table 1, ACMG SF v2.0 genes and associated phenotypes recommended for return of secondary findings

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 0.004 Open source ↗
ClinVar Captured ClinVar source record 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

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.396. BayesDel score = -0.187387.

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 previously been reported in somatic cancers (COSMIC; COSV58783414, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.