Classification rationale

BS1BP4 Likely Benign

BRCA2 c.9257G>C missense · exon 25

BS1 Strong: the maximum non-cancer filter allele frequency is 0.00043582, above the ENIGMA threshold of 0.0001. BP4 Supporting: BayesDel -0.0288497 and SpliceAI 0.011 meet the ENIGMA BRCA2 no-impact thresholds.

BS1 + BP4 → 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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 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

BS1 strong Benign

Met at strong: maximum non-cancer grpmax FAF was 0.00043582, exceeding the ENIGMA BS1 threshold of 0.0001.

gnomAD v2.1 non-cancer exomes: maximum non-cancer grpmax FAF 0.00043582, from 20 alternate alleles among 235466, with one homozygote.gnomAD v3.1 non-cancer genomes: maximum non-cancer grpmax FAF 0.00028352, from 4 alternate alleles among 147624, with zero homozygotes.The governing ENIGMA BRCA2 specification assigns BS1 Strong above FAF 0.0001 and BS1 Supporting only above 0.00002 through 0.0001.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Met, Supporting: BayesDel -0.0288497 is <=0.18 and SpliceAI 0.011 is <=0.1, satisfying both BRCA2 BP4 no-impact requirements.

The ENIGMA VCEP defines BP4 for missense variants inside a clinically important functional domain only when BayesDel predicts no impact and SpliceAI is <=0.1; BRCA2 no-impact BayesDel cutoff is 0.18.BayesDel no-AF score for NM_000059.4:c.9257G>C is -0.0288497, meeting the VCEP BRCA2 no-impact cutoff of <=0.18.SpliceAI maximum delta score is 0.011, meeting the VCEP no-predicted-splicing cutoff of <=0.1.

cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 Not assessed: SpliceAI max delta 0.011 meets the <=0.1 requirement, but no qualifying pathogenic same-amino-acid reference variant was found.

PS3 Not assessed: no qualifying calibrated protein-function result was found, while the available variant-specific assay was mRNA-only and showed no splicing abnormality.

PS4 Not assessed: no exact variant-level case-control p-value, OR, or confidence interval was available to test the ENIGMA PS4 thresholds.

PM2 Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 8.4938e-05 and gnomAD v3.1 non-cancer genomes at AF 2.7096e-05.

PM3 Not met: gnomAD maximum FAF is 0.00043457, exceeding the VCEP benign-evidence threshold of 0.0001, and no Fanconi-anemia proband with a same-gene co-occurring variant is documented.

PP1 Not assessed: no variant-specific pedigree or quantitative segregation likelihood ratio was available to compare with the VCEP's PP1 threshold of LR ≥2.08:1.

PP3 Not met: BayesDel -0.0288497 is below the 0.30 PP3 threshold and SpliceAI 0.011 is below the 0.2 splice threshold.

PP4 Not assessed: no exact combined clinical likelihood ratio was available to test the ENIGMA PP4 threshold of LR ≥2.08:1.

Benign

BA1 Not met: maximum non-cancer grpmax FAF was 0.00043582, below the ENIGMA BA1 threshold of 0.001.

BS2 Not assessed: one gnomAD homozygote lacks the VCEP-required phenotyped-individual and age/follow-up data for BS2.

BS3 Not assessed: the only variant-specific assay was mRNA-only, showing no splicing abnormality but providing no calibrated evidence that the encoded protein is functionally benign.

BS4 Not assessed: no variant-specific pedigree or quantitative negative-segregation likelihood ratio was available to compare with the VCEP's BS4 threshold of LR ≤0.48:1.

BP5 Not assessed: no exact combined clinical LR was available to test the ENIGMA BP5 operator LR ≤0.48:1.

N/A · 13 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.97662e-05; MAF= 0.00298%, 48/1612568 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000528239; MAF= 0.05282%, 48/90868 alleles, homozygotes = 1); grpmax FAF= 0.00040896.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.00576e-05; MAF= 0.00801%, 20/249820 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000656858; MAF= 0.06569%, 20/30448 alleles, homozygotes = 1); grpmax FAF= 0.00043457.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.003% · 48 / 1,612,568
1 hom · FAF 0.041%

South Asian

48 / 90,868

0.053%

1 hom

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.008% · 20 / 249,820
1 hom · FAF 0.043%

South Asian

20 / 30,448

0.066%

1 hom

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 156179)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.619. BayesDel score = -0.0288497.

SpliceAI ↗

Functional Likely Neutral

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Diagnostic mRNA splicing assay for variants in BRCA1 and BRCA2 identified two novel pathogenic splicing aberrations.

PMID 31143303 ↗ · Wangensteen T et al. · 2019 CLINVAR · functional

Searched

c.9257G>Cc.9257G > Cp.(Gly3086Ala)p.Gly3086Alap.G3086A

Found

The paper explicitly reports BRCA2 c.9257G>C, p.(Gly3086Ala) as an exonic amino-acid substitution analyzed by an mRNA splicing assay. It was classified as splice class 1S, indicating no observed effect on splicing with both alleles identified using informative SNPs; the authors state that protein-function impact requires separate assessment.

Variant

✓ Names this variant — characterised directly

Applied to

→BP4 supporting

Variant-specific mRNA assay context reports normal splicing and is concordant with the BP4 no-splice prediction, without replacing the VCEP SpliceAI requirement.

BRCA2 c.9257G > C p.(Gly3086Ala)

Location Table 2; Discussion, paragraph beginning ‘Sixteen variants showed normal splicing.’ · Context Patient blood RNA mRNA splicing assay using reverse transcription-PCR, fragment analysis, sequencing, and assessment of biallelic expression; variant reported as splice class 1S. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

35736817 ↗ Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. ONCOKB

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

38417439 ↗ Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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