BRCA2

Final classification

Likely Benign

BRCA2 c.1501A>G · p.Ile501Val

BRCA2

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.1501A>G

Consequence

N/A

GRCh38

chr13:32332979 A>G

GRCh37

chr13:32907116 A>G

Basis ENIGMA BRCA2 VCEP v1.2.0 conflicting-evidence point system: PM2_Supporting (+1 pathogenic point) and BP1_Strong (-4 benign point) = -3 total points, which falls in the Likely Benign range (-6 to -2). Both pathogenic and benign criteria are met, triggering the ENIGMA Table 3 point-based conflicting evidence rule. ▾

ENIGMA BRCA2 VCEP v1.2.0 conflicting-evidence point system: PM2_Supporting (+1 pathogenic point) and BP1_Strong (-4 benign point) = -3 total points, which falls in the Likely Benign range (-6 to -2). Both pathogenic and benign criteria are met, triggering the ENIGMA Table 3 point-based conflicting evidence rule.

Classification rationale

PM2 BP1 Likely Benign

BRCA2 c.1501A>G

BP1_Strong is met: c.1501A>G (p.Ile501Val) is a missense variant located at amino acid 501, outside both BRCA2 clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), with no predicted splicing impact (SpliceAI max delta 0.0).¹ PM2_Supporting is met: the variant is absent from gnomAD v2.1 (non-cancer, exome) and observed as a single allele in gnomAD v4.1 (AF=6.27e-07), which ENIGMA deems not informative for an outbred population.² No pathogenic criteria beyond PM2_Supporting were met. PVS1, PS1, PS3, PS4, PP1, PP3, and PP4 are all not met or not applicable for this missense variant.³ In silico predictions are consistent with a benign interpretation: BayesDel no-AF score -0.472575 and REVEL 0.228 are below pathogenic thresholds. The variant is not in a functional domain, not at a hotspot, and was not identified in any calibrated functional assay (ENIGMA Table 9).⁴ ClinVar reports this variant as Uncertain Significance (4 submitters) and Likely Benign (1 submitter), with no expert panel classification (ClinVar VariationID: 433760).⁵

PM2 + BP1 → Likely Benign

1 cspec ↗spliceai ↗PMID:31911673 ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗

4 bayesdelrevelvcep_specifications_table9_v1_2_2024_11_18

5 clinvar ↗

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

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting review Pathogenic

The variant is absent from gnomAD v2.1 (non-cancer, exome). In gnomAD v4.1, it is observed as a single allele (AF=6.27e-07, 1/1,595,636) in the European (non-Finnish) population. Per ENIGMA guidance, a single observation in a gnomAD outbred population is not informative and does not preclude PM2_Supporting. The variant is also absent from gnomAD-Canada.

Absent from gnomAD v2.1 (non-cancerexome only).Single allele in gnomAD v4.1 (AF=6.27e-07

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

✓

BP1 strong Benign

ENIGMA BP1_Strong applies to missense variants outside a (potentially) clinically important functional domain with no predicted splicing impact (SpliceAI ≤ 0.1). This missense variant (p.Ile501Val) is at amino acid position 501, which is outside both BRCA2 clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). SpliceAI max delta is 0.0, indicating no splicing impact. BRCA2 exons 10 and 11 (codons 266-2281) contain 0 P/LP missense variants among 2,177 submitted to ClinVar, consistent with this region being a validated coldspot.

Missense variant at position 501outside PALB2 binding domain (aa 10-40) and DNA binding domain (aa 2481-3186).SpliceAI max delta 0.0 — no splicing impact.

cspec ↗spliceai ↗PMID:31911673 ↗

Assessed · not applied

Pathogenic

PS1 No previously classified pathogenic or likely pathogenic variant with the same amino acid change (p.Ile501Val) was identified.

PS3 This variant was not identified in the ENIGMA Specifications Table 9 curated functional assay results.

PS4 No case-control study demonstrating significantly increased prevalence in affected individuals was identified.

PP1 No co-segregation data or quantitative likelihood ratio analysis is available for this variant.

PP3 ENIGMA PP3 requires either (a) a missense variant inside a clinically important functional domain with BayesDel no-AF ≥ 0.30, or (b) SpliceAI ≥ 0.2.

PP4 ENIGMA PP4 requires a combined likelihood ratio from multifactorial clinical data (LR ≥ 2.08 for Supporting).

Benign

BA1 ENIGMA BA1 requires FAF > 0.1% (0.001) in gnomAD non-founder populations.

BS1 ENIGMA BS1_Supporting requires FAF > 0.002% (0.00002) and BS1_Strong requires FAF > 0.01% (0.0001).

BS2 ENIGMA BS2 requires co-occurrence of the variant in trans with a known P/LP variant in the same gene, with absence of Fanconi Anemia phenotype, scored per Specifications Table 8.

BS3 The variant was not identified in the ENIGMA Specifications Table 9 curated functional assay results assigning BS3 codes.

BS4 ENIGMA BS4 requires lack of segregation in affected family members as measured by quantitative co-segregation analysis (LR ≤ 0.48 for Supporting).

BP4 ENIGMA BP4_Supporting applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≤ 0.18 and SpliceAI ≤ 0.1.

BP5 ENIGMA BP5 requires a combined likelihood ratio against pathogenicity from multifactorial clinical data (LR ≤ 0.48 for Supporting).

BP7 ENIGMA BP7_Strong (RNA) requires well-established mRNA functional studies showing no damaging effect.

N/A · 9 PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.26709e-07; MAF= 0.00006%, 1/1595636 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.50706e-07; MAF= 0.00009%, 1/1175494 alleles, homozygotes = 0).

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

6.3e-05% · 1 / 1,595,636
0 hom

European (non-Finnish)

1 / 1,175,494

8.5e-05%

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

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 has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 433760)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.228. BayesDel score = -0.472575.

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 ↗

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. 6 further PMIDs triaged but not cited — see Sources & References.

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

PMID 31911673 ↗ · Dines JN et al. · 2020 May CLINVAR · functional

Searched

c.1501A>Gp.Ile501ValI501VIle501Val1501

Found

Evaluated BRCA1 and BRCA2 missense variants in ClinVar to identify coldspot regions. In BRCA2 exons 10 and 11 (codons 266-2281), 0 of 2,177 missense variants were classified as pathogenic or likely pathogenic, establishing this region as a coldspot. Proposed that missense variants in coldspots can be classified as likely benign using Bayesian odds ratio thresholds.

Variant

◇ Residue / gene-level — variant not named

Applied to

→BP1 supports · met

Why

Variant not specifically mentioned, but paper provides foundational coldspot evidence supporting BP1_Strong application for missense variants in BRCA2 exon 10 (codon 501). 0/2177 P/LP missense variants in this region.

Exon 10 and 11 ... 0 (0) ... 110 (5.1) ... 2067 (94.9) ... 2177 (100.0)

Location Table 1; Results, BRCA2 section · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

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

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

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

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

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

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