Variant classification summary

NM_000059.4:c.5946del

BRCA2 · NP_000050.3:p.(Ser1982ArgfsTer22) · NM_000059.4

GRCh37: chr13:32914437 GT>G · GRCh38: chr13:32340300 GT>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM5 strong PP4 strong PP5 supporting BS1 supporting benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ser1982ArgfsTer22)

gnomAD AF

0.00013941574270174079 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 resulting in a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay, in a gene where loss of function is an established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight.

2

ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 11, indicating additional pathogenic weight for a protein termination codon variant in an exon where other proven pathogenic PTC variants have been previously observed.

3

Clinical-history likelihood ratio analysis from Li et al. 2020 (PMID:31853058) yields an LR of 31.79 based on 149 carriers, exceeding the ENIGMA PP4_Strong threshold of ≥18.7:1. The personal and family cancer history profile of individuals carrying this variant is significantly enriched for breast and ovarian cancer compared to non-carriers.

4

The variant is present in gnomAD population databases at low frequency in non-founder populations (grpmax FAF=5.39e-05 in v2.1, 2.154e-05 in v4.1), meeting ENIGMA BS1_Supporting (FAF >0.002% and ≤0.01%). The higher Ashkenazi Jewish allele frequency (0.589%) is attributable to a known founder effect and is excluded from BS1/BA1 assessment per ENIGMA non-founder population rules.

5

This variant has been reported in ClinVar as Pathogenic by 67 clinical laboratories and by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 9325). The variant has been observed in multiple affected individuals across diverse populations and has been described as a recurrent pathogenic founder mutation.

6

Under ENIGMA Table 3 combining rules, the combination of PVS1 (Very Strong) + PM5 (Strong) satisfies the Pathogenic classification threshold (1 Very Strong + ≥1 Strong). PP4 (Strong) provides additional corroborating evidence. BS1_Supporting does not alter the pathogenic classification.

Final determination: ENIGMA Table 3 point system: net +16 points (PVS1 Very Strong +8, PM5 Strong +4, PP4 Strong +4, PP5 Supporting +1, BS1 Supporting Benign -1) meets Pathogenic threshold (>=10); the 1 Very Strong + >=1 Strong all_of rule is also independently satisfied.

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	Met	NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 predicted to cause a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay. Loss of function is an established disease mechanism for BRCA2 in hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight; the variant occurs upstream of the DNA-binding domain (aa 2481-3186) and is not in a PVS1-downgraded region.	vcep_specifications_table4_v1_2_2024_11_18 cspec pvs1_generic_framework
PS1	N/A	PS1 per ENIGMA applies to predicted missense substitutions with a previously classified pathogenic comparator acting via the same protein change, or to exonic/intronic variants with the same predicted splicing impact as a known pathogenic variant. This is a frameshift PTC variant and does not fall under either PS1 rule.
PS2	N/A	PS2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
PS3	Not assessed	ENIGMA Table 9 (curated functional assay results) applies to missense and synonymous variants and contains no entry for this frameshift PTC variant. Frameshift null variants in BRCA2 are inherently loss-of-function; dedicated PS3 functional evidence is not required for classification.
PS4	Not assessed	ENIGMA PS4 requires a formal case-control study with p-value ≤0.05, OR ≥4, and lower CI excluding 2.0. While the variant has been widely observed in affected individuals (149 probands in Li et al. 2020 clinical-history dataset; ClinVar reports 67 clinical laboratories classifying as Pathogenic), no published case-control study meeting ENIGMA PS4 specifications is available in the evidence packet.	clinvar PMID:31853058
PS5	N/A	PS5 is not an active criterion under the ENIGMA BRCA2 VCEP specification.
PM1	N/A	PM1 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
PM2	Not met	ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome) and gnomAD v3.1 (non-cancer) in outbred populations. This variant is present in gnomAD v2.1 (AF=0.02765%, 78/282088 alleles) and gnomAD v4.1 (AF=0.01394%, 225/1613878 alleles), including presence in non-founder populations (grpmax FAF=5.39e-05 in v2.1). PM2 is therefore not met.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
PM5	Met	This is a protein termination codon (PTC) variant in BRCA2 exon 11. Per ENIGMA Specifications Table 4, exon 11 is assigned PM5_Strong (PTC), indicating that other proven pathogenic PTC variants have been previously observed in this exon. The variant qualifies for PVS1 and PM5_PTC provides additional weight.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	PM6 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
PP1	Not assessed	ENIGMA PP1 requires quantitative co-segregation analysis with LR thresholds (Supporting ≥2.08, Moderate ≥4.3, Strong ≥18.7). Exploratory evidence suggests the variant may co-segregate with disease in families, but full-text verification of variant-specific segregation data was not possible (available full-text files were Sci-Hub boilerplate without paper content). No pedigree-level co-segregation LR is available in the evidence packet.
PP2	N/A	PP2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
PP3	N/A	ENIGMA PP3 applies to missense/in-frame variants inside clinically important functional domains with BayesDel ≥0.30, or to variants with predicted splicing impact (SpliceAI ≥0.2) for silent/missense/in-frame/intronic variants. This is a frameshift PTC variant with SpliceAI max delta score of 0.00; PP3 criteria are not applicable. Per ENIGMA, PP3 is not stacked on PVS1 for the same splice-effect evidence.	spliceai
PP4	Met	Clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=31.79 based on 149 probands. This exceeds the ENIGMA PP4_Strong threshold of ≥18.7:1, indicating that the personal and family cancer history profile of carriers is significantly enriched for pathogenicity.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	clinvar
BA1	Not met	ENIGMA BA1 (Stand-Alone benign) requires FAF > 0.1% in gnomAD non-founder populations. The grpmax FAF for this variant is 5.39e-05 (0.00539%) in gnomAD v2.1 and 2.154e-05 (0.00215%) in gnomAD v4.1, both well below the 0.1% threshold. The elevated Ashkenazi Jewish AF (0.589%) is attributable to a known founder effect and is excluded per ENIGMA's non-founder population stipulation.	gnomad_v2 gnomad_v4
BS1	Met	ENIGMA BS1_Supporting applies when FAF > 0.002% and ≤0.01% in gnomAD non-founder populations. The grpmax FAF is 5.39e-05 (0.00539%) in gnomAD v2.1, which falls within this range. The variant is observed in outbred population controls at a low but non-negligible frequency, providing supporting evidence that it may be more common than expected for a highly penetrant pathogenic variant.	gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA BS2 is applied in the absence of features of recessive Fanconi anemia (FA) phenotype in individuals carrying the variant. While most heterozygous carriers do not exhibit FA, BS2 requires systematic data on the absence of FA features in observed carriers. No such systematic dataset is available in the evidence packet.
BS3	Not assessed	ENIGMA BS3 applies when well-established functional studies show no damaging effect on protein function. ENIGMA Table 9 lists pre-assigned BS3 codes for missense/synonymous variants only. This frameshift PTC variant is predicted to cause complete loss of function via protein truncation and NMD; no functional evidence of a benign effect exists or is expected.
BS4	Not assessed	ENIGMA BS4 requires quantitative lack-of-segregation analysis (LR ≤0.48 for Supporting). No variant-specific non-segregation data is available in the evidence packet. The variant is a known pathogenic founder mutation; segregation data, if it exists, would more likely support pathogenicity.
BP1	N/A	ENIGMA BP1 applies to silent substitutions, missense variants, or in-frame insertions/deletions/delins variants outside clinically important functional domains with no splicing predicted. This is an out-of-frame frameshift deletion producing a PTC, not an in-frame variant, and is therefore not eligible for BP1.
BP2	N/A	BP2 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
BP3	N/A	BP3 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
BP4	N/A	ENIGMA BP4 applies to missense/in-frame variants inside clinically important functional domains with no predicted impact (BayesDel ≤0.18 and SpliceAI ≤0.1), or to silent/intronic variants with no splicing predicted. This is a frameshift PTC variant, not a missense/in-frame/silent variant; BP4 is not applicable.
BP5	Not met	ENIGMA BP5 captures clinical-history LR against pathogenicity. The clinical-history LR from Li et al. 2020 is 31.79 (pathogenic direction). BP5 requires LR ≤0.48 for Supporting, which is not satisfied. The data strongly favor pathogenicity, not benignity.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is marked Not Applicable by the ENIGMA BRCA2 VCEP specification.
BP7	N/A	ENIGMA BP7 applies to silent/intronic variants or to well-established functional mRNA studies showing no damaging effect on splicing. This is a frameshift PTC variant with SpliceAI max delta 0.00; BP7 does not apply. ENIGMA BP7 (RNA) is for intronic/silent/missense/in-frame variants with mRNA assay evidence, not for frameshift null variants.

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