Variant classification summary

NM_000059.4:c.1501A>G

BRCA2 · NP_000050.3:p.(Ile501Val) · NM_000059.4

GRCh37: chr13:32907116 A>G · GRCh38: chr13:32332979 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

PM2 supporting BP1 strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile501Val)

gnomAD AF

6.267093497514471e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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.

3

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.

4

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).

5

ClinVar reports this variant as Uncertain Significance (4 submitters) and Likely Benign (1 submitter), with no expert panel classification (ClinVar VariationID: 433760).

Final determination: ENIGMA Table 3 conflicting-evidence point system: PM2_Supporting (+1) + BP1_Strong (-4) = -3 points, falling in the Likely Benign range (-6 to -2).

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is defined for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, exon deletions) per ENIGMA BRCA2 specifications. NM_000059.4:c.1501A>G is a missense variant (p.Ile501Val) and does not qualify.	cspec
PS1	Not met	No previously classified pathogenic or likely pathogenic variant with the same amino acid change (p.Ile501Val) was identified. SpliceAI predicts no splicing impact (max delta 0.0), excluding the splicing-based PS1 pathway.	cspec spliceai
PS2	N/A	PS2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specifications.	cspec
PS3	Not met	This variant was not identified in the ENIGMA Specifications Table 9 curated functional assay results. No variant-specific functional studies demonstrating a damaging effect on protein function were found in the literature.	cspec vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not met	No case-control study demonstrating significantly increased prevalence in affected individuals was identified. The variant is not present in the ENIGMA Supplementary Table 7 reference set and lacks case-control OR data.	cspec vcep_supplementarytables_v1_2_2024_11_18
PS5	N/A	PS5 is not a defined criterion in the ACMG/AMP framework. PP5 is Not Applicable per ENIGMA BRCA2 VCEP specifications (not for use as recommended by the ClinGen SVI VCEP Review Committee).	cspec
PM1	N/A	PM1 is captured as a component of bioinformatic analysis under PP3/BP4 per ENIGMA BRCA2 VCEP specifications. The variant resides at amino acid position 501, which is outside both clinically important functional domains (BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding domain aa 2481-3186).	cspec
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	ENIGMA BRCA2 VCEP repurposes PM5 exclusively for protein termination codon (PTC) variants in exons where a different proven pathogenic PTC has been observed. NM_000059.4:c.1501A>G is a missense variant (p.Ile501Val), not a PTC.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is marked Not Applicable by the ENIGMA BRCA2 VCEP specifications.	cspec
PP1	Not met	No co-segregation data or quantitative likelihood ratio analysis is available for this variant. ENIGMA requires LR ≥ 2.08 for PP1_Supporting from a quantitative co-segregation method.	cspec
PP2	N/A	PP2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specifications.	cspec
PP3	Not met	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. The variant is at position 501, outside both clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). BayesDel no-AF score is -0.472575 (< 0.30). SpliceAI max delta is 0.0 (< 0.2). Neither condition is satisfied.	cspec bayesdel spliceai revel
PP4	Not met	ENIGMA PP4 requires a combined likelihood ratio from multifactorial clinical data (LR ≥ 2.08 for Supporting). The variant was not found in the Li et al. 2020 clinical-history LR table (PMID:31853058), the Parsons et al. 2019 multifactorial analysis (HUMU-40-1557-s001), or the ENIGMA ST7 reference set. No clinical-history or multifactorial LR data are available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP5	N/A	PP5 is Not Applicable per ENIGMA BRCA2 VCEP specifications. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	ENIGMA BA1 requires FAF > 0.1% (0.001) in gnomAD non-founder populations. The variant has an allele frequency of 8.51e-07 (0.000085%) in the European (non-Finnish) population in gnomAD v4.1 and is absent from gnomAD v2.1. This is far below the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Supporting requires FAF > 0.002% (0.00002) and BS1_Strong requires FAF > 0.01% (0.0001). The highest observed AF is 8.51e-07 in gnomAD v4.1 NFE, far below the BS1_Supporting threshold of 0.00002. FAF values are not available from gnomAD for this variant.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	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. No such co-occurrence data are available for this variant.	cspec
BS3	Not met	The variant was not identified in the ENIGMA Specifications Table 9 curated functional assay results assigning BS3 codes. No well-established functional studies demonstrating no damaging effect on protein function were found in the literature.	cspec vcep_specifications_table9_v1_2_2024_11_18 oncokb
BS4	Not met	ENIGMA BS4 requires lack of segregation in affected family members as measured by quantitative co-segregation analysis (LR ≤ 0.48 for Supporting). No segregation data are available for this variant. The variant is not present in the ENIGMA ST7 reference set or the Parsons et al. 2019 multifactorial analysis.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	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.	cspec spliceai PMID:31911673
BP2	N/A	BP2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specifications.	cspec
BP4	Not met	ENIGMA BP4_Supporting applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≤ 0.18 and SpliceAI ≤ 0.1. Position 501 is outside both clinically important functional domains. For missense variants outside domains, the bioinformatic evidence is captured by BP1_Strong rather than BP4.	cspec bayesdel spliceai
BP5	Not met	ENIGMA BP5 requires a combined likelihood ratio against pathogenicity from multifactorial clinical data (LR ≤ 0.48 for Supporting). The variant was not found in the Li et al. 2020 clinical-history LR table, the Parsons et al. 2019 multifactorial analysis, or the ENIGMA ST7 reference set. No clinical-history or multifactorial LR data are available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP6	N/A	BP6 is marked Not Applicable by the ENIGMA BRCA2 VCEP specifications.	cspec
BP7	Not met	ENIGMA BP7_Strong (RNA) requires well-established mRNA functional studies showing no damaging effect. No such data are available. ENIGMA BP7_Supporting applies to silent variants inside domains (if BP4 met) or intronic variants beyond +7/-21 (if BP4 met). This missense variant does not qualify for either BP7 pathway.	cspec

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