Classification rationale

BP1BP6 Likely Benign

BRCA2 c.7317A>G synonymous · exon 14

BP1 (Strong): synonymous change at codon 2439, outside the PALB2-binding and DNA-binding domains, with no predicted splice impact (SpliceAI max delta 0.012). BP6 (Supporting): ENIGMA expert panel classified this exact variant Likely benign (ClinVar SCV000579037). Likely Benign: ENIGMA CSPEC v1.2 Table 3 combines BP1 (Strong) with BP6 (Supporting), both benign-direction, with no pathogenic criteria met.

BP1 + BP6 → Likely Benign

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

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

✓

BP1 strong review Benign

Met (Strong): silent change at codon 2439, outside the PALB2-binding (aa10-40) and DNA-binding (aa2481-3186) domains, with SpliceAI max delta 0.012 ≤ 0.1.

ENIGMA BRCA1/BRCA2 CSPEC v1.2 BP1 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). ... clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.'Variant normalizes to NP_000050.3:p.(Gly2439=), residue 2439, which lies outside both the PALB2-binding domain (aa 10-40) and the DNA-binding domain (aa 2481-3186).SpliceAI predicts no significant splice impact for this variant (max delta score = 0.012 / 0.01), from case prefetch/evidence data, satisfying the SpliceAI ≤0.1 requirement.

cspec ↗spliceai ↗

✓

BP6 supporting Benign

Met (Supporting): ENIGMA expert panel classified this exact variant Likely benign (ClinVar SCV000579037).

ClinVar Variation ID 135813 is an exact transcript-HGVS match for NM_000059.4:c.7317A>G (p.Gly2439=).The exact-match audit identifies ENIGMA submission SCV000579037 as an expert-panel assertion with classification Likely benign.ClinVar expert panel classification

clinvar ↗

Assessed · not applied · 7 not met · 9 not assessed

Pathogenic

PS3 Insufficient evidence: no functional assay result (minigene, saturation genome editing, or protein-based) for this variant was available.

PS4 Insufficient evidence: no case-control enrichment study reporting this exact variant was available.

PM2 Not met: the variant is present in gnomAD v2.1 (7/251,214 alleles; AF 2.8e-05), so the PM2 absence-from-controls requirement is not satisfied.

PM3 Insufficient evidence: no Fanconi anemia phenotype, second BRCA2 variant, or inheritance data were available to assess PM3.

PP1 Insufficient evidence: no family segregation data or quantitative co-segregation likelihood ratio were available.

PP3 Not met: SpliceAI max delta 0.012 is far below the ≥0.2 PP3 splice-impact threshold for silent variants.

PP4 Insufficient evidence: no ENIGMA multifactorial clinical-history likelihood ratio for this variant was available.

PP5 Not met: the sole ClinVar expert-panel entry is ENIGMA Likely benign, not Pathogenic or Likely pathogenic.

Benign

BA1 Not met: maximum gnomAD non-founder FAF is 1.687e-05, far below the >0.001 BA1 threshold.

BS1 Not met: gnomAD v2.1 maximum population FAF 1.687e-05 falls below the BS1 Supporting lower bound of 0.00002.

BS2 Insufficient evidence: no identifiable healthy adult probands or co-occurrence variables were available to assign BS2 points.

BS3 Insufficient evidence: no functional assay demonstrating a benign effect for this variant was available.

BS4 Insufficient evidence: no family testing showing lack of segregation with disease was available.

BP4 Not met: SpliceAI is benign (max delta 0.012 ≤ 0.1), but BP4's silent-variant rule requires a position inside a functional domain; codon 2439 lies outside both.

BP5 Insufficient evidence: no ENIGMA likelihood ratio against pathogenicity for this variant was available.

BP7 Not met: BP7 requires a silent variant inside a functional domain with BP4 met; codon 2439 lies outside both domains.

N/A · 10 PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.53193e-05; MAF= 0.00353%, 57/1613848 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.33222e-05; MAF= 0.00833%, 5/60008 alleles, homozygotes = 0); grpmax FAF= 3.233e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.78647e-05; MAF= 0.00279%, 7/251214 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.78269e-05; MAF= 0.00578%, 2/34586 alleles, homozygotes = 0); grpmax FAF= 1.687e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0035% · 57 / 1,613,848
0 hom · FAF 0.0032%

Admixed American 5 / 60,008	0.0083%
European (non-Finnish) 48 / 1,179,886	0.0041%
Remaining individuals 2 / 62,470	0.0032%
African/African American 2 / 74,924	0.0027%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0028% · 7 / 251,214
0 hom · FAF 0.0017%

Admixed American 2 / 34,586	0.0058%
European (non-Finnish) 5 / 113,544	0.0044%

+ 6 not observed (African/African 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 Likely benign (8 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 135813)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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 · 9 PMIDs not cited in assessment

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

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

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

21918853 ↗ Low prevalence of BRCA1 and BRCA2 mutations in the sporadic breast cancer of Spanish population. CLINVAR

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

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

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

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