Classification rationale

BP1 Likely Benign

BRCA2 c.3941A>G missense · exon 11

Likely Benign: BP1 Strong is supported by the residue being outside critical BRCA2 domains and SpliceAI maximum delta of 0.001.

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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 15 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 · 1

Strength Supporting Moderate Strong Very strong

BP1 strong Benign

Met, strong: residue 1314 is outside ENIGMA critical domains and SpliceAI max delta is 0.001, below the <=0.1 threshold.

ENIGMA BRCA2 VCEP BP1_Strong requires a missense variant outside a potentially clinically important functional domain and SpliceAI <=0.1.The VCEP critical domains are BRCA2 PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 1314 is outside both.The case SpliceAI maximum delta score is 0.001, satisfying the VCEP <=0.1 no-splicing-predicted requirement.

cspec ↗spliceai ↗

Assessed · not applied · 5 not met · 10 not assessed

Pathogenic

PVS1 Not met: c.3941A>G is a missense variant, whereas ENIGMA PVS1 is restricted to null variants such as nonsense, frameshift, or canonical splice changes.

PS1 Not met: the exact variant was reported once as unclassified, with no pathogenic same-amino-acid comparator identified under the ENIGMA PS1 rule.

PS3 Not assessed: no VCEP Table 9 entry or validated damaging protein assay was found for c.3941A>G; the reported paper labels its effect unknown.

PS4 Not assessed: no variant-specific case-control OR, p-value, or confidence interval was available to evaluate the PS4 thresholds p-value <=0.05 and OR >=4.

PM2 Not met: the variant is observed once in gnomAD v2.1 non-cancer exomes (1/208114), so it is not absent from both required control datasets.

PM3 Not assessed: one family report lacks the VCEP-required Fanconi-anemia phenotype and pathogenic BRCA2 co-occurrence or phase information.

PP1 Not assessed: no affected-relative segregation data or quantitative LR is available, and the ENIGMA PP1 supporting threshold is LR ≥2.08:1.

PP3 Not met: SpliceAI maximum delta 0.001 is below the ENIGMA PP3 threshold of >=0.2, and BayesDel -0.521046 is below the >=0.30 protein-impact threshold.

PP4 Not assessed: no exact-variant combined clinical LR was available to compare with the PP4 Supporting threshold LR >=2.08.

Benign

BA1 Not met: the highest reported population frequency is 2.77346e-05, far below the ENIGMA BA1 threshold of 0.001.

BS1 Not assessed: non-cancer allele frequency reaches 2.77346e-05, but the VCEP-required filter allele frequency is unavailable.

BS2 Not assessed: gnomAD shows zero homozygotes, but no eligible healthy-adult observation or VCEP Table 8 point assignment is documented.

BS3 Not assessed: no VCEP Table 9 entry or validated benign protein assay was found for c.3941A>G; the reported paper labels its effect unknown.

BS4 Not assessed: no non-segregating affected relatives or quantitative LR is available, and the ENIGMA BS4 supporting threshold is LR ≤0.48:1.

BP5 Not assessed: no exact-variant combined LR was available to evaluate the BP5 Supporting inequality LR <=0.48.

N/A · 12 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · 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= 2.5333e-06; MAF= 0.00025%, 4/1578966 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.4335e-06; MAF= 0.00034%, 4/1164992 alleles, homozygotes = 0); grpmax FAF= 8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.51076e-06; MAF= 0.00045%, 1/221692 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.73539e-06; MAF= 0.00097%, 1/102718 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00025% · 4 / 1,578,966
0 hom · FAF 8e-05%

European (non-Finnish)

4 / 1,164,992

0.00034%

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

gnomAD v2.1

0.00045% · 1 / 221,692
0 hom

European (non-Finnish)

1 / 102,718

0.00097%

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

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 (4 clinical laboratories). (ClinVarID = 479275)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.067. BayesDel score = -0.521046.

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. BRCA2, 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 not previously been reported in somatic cancers (COSMIC).

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 · 8 PMIDs not cited in assessment

16683254 ↗ A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. 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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR

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

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR

31429903 ↗ Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR

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