Classification rationale

PM2 BP1 Likely Benign

BRCA1 c.2927A>G missense · exon 10

PM2 supporting: the variant is absent from the preferred non-cancer gnomAD exome and genome datasets. BP1 strong: residue 976 lies outside ENIGMA BRCA1 functional domains and SpliceAI maximum delta is 0.004.

PM2 + BP1 → Likely Benign

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.

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

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

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.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP1 strong Benign

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

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.

cspec ↗spliceai ↗

Assessed · not applied · 6 not met · 10 not assessed

Pathogenic

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

PS3 Not assessed: no variant-specific calibrated damaging functional assay result or ENIGMA PS3 assignment was found for c.2927A>G.

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.

PM3 Not assessed: no Fanconi-anemia phenotype, second BRCA1 pathogenic allele, or phase observation is documented for PM3 point assignment.

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.

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.

PP4 Not assessed: no variant-specific combined clinical likelihood ratio was available for comparison with the PP4 Supporting threshold LR >=2.08.

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.

Benign

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.

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.

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.

BS3 Not assessed: no variant-specific calibrated benign functional assay result or ENIGMA BS3 assignment was found for c.2927A>G.

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.

BP4 Not met: REVEL 0.396 exceeds the <=0.29 supporting BP4 threshold and remains in the gray zone for benign protein impact.

BP5 Not assessed: no variant-specific combined LR was available to test the BP5 Supporting inequality LR <=0.48 and >0.23.

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.

N/A · 10 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

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.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58783414, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

20065170 ↗ American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. CLINVAR

23188549 ↗ NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

27854360 ↗ 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. CLINVAR

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