Variant classification summary

NM_000059.4:c.8673_8674del

BRCA2 · NP_000050.3:p.(Arg2892ThrfsTer14) · NM_000059.4

GRCh37: chr13:32950846 CAA>C · GRCh38: chr13:32376709 CAA>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting PP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Arg2892ThrfsTer14)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.8673_8674del is a 2-bp frameshift deletion in BRCA2 exon 21 (DNA-binding domain, aa 2481-3186), producing a premature termination codon p.Arg2892ThrfsTer14. BRCA2 loss of function is a well-established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4 v1.2, PTC variants in exon 21 receive PVS1 at Very Strong strength.

2

The variant is absent from gnomAD v2.1 and v4.1 population databases, supporting pathogenicity (PM2 at Supporting strength per ENIGMA).

3

Per ENIGMA Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon.

4

ClinVar classifies this variant as Pathogenic with 3-star expert panel review by ENIGMA (Variation ID 52656). PP5 is met at Supporting strength.

5

Using the ENIGMA point system: PVS1 (Very Strong = 8) + PM2 (Supporting = 1) + PM5 (Supporting = 1) + PP5 (Supporting = 1) = 11 points. Score ≥10 meets the ENIGMA Pathogenic threshold. This also satisfies the ENIGMA Table 3 rule requiring 1 Very Strong criterion plus at least 2 Supporting criteria for Pathogenic classification.

Final determination: ENIGMA Table 3 Pathogenic rule: 1 Very Strong criterion (PVS1) combined with ≥2 Supporting criteria (PM2, PM5, PP5) classifies as Pathogenic. Confirmed by ENIGMA point system: 11 points ≥ 10 threshold for Pathogenic.

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.8673_8674del is a 2-bp deletion in exon 21 causing a frameshift that produces p.Arg2892ThrfsTer14, a premature termination codon (PTC). Loss of function is an established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PVS1 at full (Very Strong) strength. The truncation removes 526 C-terminal amino acids including OB folds and nuclear localization signals within the DNA-binding domain (aa 2481-3186), and is predicted to trigger nonsense-mediated decay.	cspec vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 in ENIGMA applies to predicted missense substitutions or variants with same predicted impact on splicing. This is a frameshift variant.	cspec
PS2	N/A	ENIGMA CSPEC marks PS2 as Not Applicable for BRCA2.	cspec
PS3	Not met	No variant-specific functional study testing NM_000059.4:c.8673_8674del was identified in the literature. OncoKB annotates this variant as Likely Loss-of-function based on curated context, but no direct experimental assay of this exact variant was found. Reviewed full-text papers discuss BRCA2 function at the gene level only. The ENIGMA Table 9 functional assay calibration covers missense and synonymous variants, not frameshift variants.	oncokb
PS4	Not met	No case-control study with odds ratio and p-value meeting ENIGMA thresholds (OR ≥4, p ≤0.05, lower CI excludes 2.0) was identified. While this variant is reported in ClinVar as Pathogenic by 16 clinical laboratories, no formal case-control study has been performed.	clinvar
PS5	N/A	PS5 is not a criterion defined in the ACMG/AMP or ENIGMA framework.
PM1	N/A	ENIGMA CSPEC explicitly marks PM1 as Not Applicable for BRCA2.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v4.1. Per ENIGMA PM2 rule, absence from population databases in an outbred population supports pathogenicity at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PM4	N/A	ENIGMA CSPEC marks PM4 as Not Applicable for BRCA2.	cspec
PM5	Met	Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon. The variant c.8673_8674del creates a PTC (p.Arg2892ThrfsTer14) in exon 21, satisfying the PM5_PTC rule.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	ENIGMA CSPEC marks PM6 as Not Applicable for BRCA2.	cspec
PP1	Not met	No co-segregation data available. ENIGMA PP1 requires quantitative co-segregation analysis with LR ≥2.08 for Supporting strength.
PP2	N/A	ENIGMA CSPEC marks PP2 as Not Applicable for BRCA2.	cspec
PP3	Not met	ENIGMA PP3 applies to missense or in-frame variants inside clinically important functional domains (BayesDel ≥0.30) or for predicted splicing (SpliceAI ≥0.2). This is a frameshift variant; BayesDel and REVEL scores are not applicable (deletion, not SNV). SpliceAI max delta = 0.0. PP3 criteria not met.	spliceai cspec
PP4	Not met	Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for this variant is LR = 1.07 (3 probands), which falls in the neutral zone (0.48 < LR < 2.08). Per ENIGMA, PP4 requires LR ≥2.08 for Supporting strength.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	clinvar cspec
BA1	Not met	Variant is absent from gnomAD. ENIGMA BA1 requires FAF > 0.1% (FAF > 0.001) in gnomAD non-founder populations. Not met as variant is absent.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD. ENIGMA BS1 requires FAF > 0.01% (Strong) or FAF > 0.002% (Supporting). Not met as variant is absent from all populations.	gnomad_v2 gnomad_v4
BS2	Not met	No proband-level data available to assess absence of Fanconi Anemia phenotype. ENIGMA BS2 requires specific proband data with points assignment per Table 8.
BS3	Not met	No variant-specific functional studies showing no damaging effect were identified. ENIGMA Table 9 covers calibrated functional assays for missense and synonymous variants; this frameshift variant is not covered. No benign functional evidence exists.
BS4	Not met	No segregation data available. ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation (LR ≤0.48 for Supporting).
BP1	N/A	ENIGMA BP1 applies to silent substitutions, missense, or in-frame variants outside clinically important functional domains. This is a frameshift variant.	cspec
BP2	N/A	ENIGMA CSPEC marks BP2 as Not Applicable for BRCA2.	cspec
BP3	N/A	ENIGMA CSPEC marks BP3 as Not Applicable for BRCA2.	cspec
BP4	Not met	ENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with no predicted impact on protein or splicing. This is a frameshift variant, not eligible for BP4 under ENIGMA rules. Additionally, SpliceAI max delta = 0.0 but the frameshift itself is predicted to be damaging.	spliceai cspec
BP5	Not met	Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for this variant is LR = 1.07 (3 probands), in the neutral zone (>0.48 and <2.08). Per ENIGMA, BP5 requires LR ≤0.48 for Supporting strength.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	ENIGMA CSPEC marks BP6 as Not Applicable. ClinVar classification is Pathogenic (not Benign/Likely Benign), so BP6 is not applicable in either direction.	cspec
BP7	N/A	ENIGMA BP7 applies to mRNA transcript-level evidence (BP7 RNA) for intronic, silent, or missense/in-frame variants outside clinically important domains. This is a frameshift variant and is not eligible for BP7 under ENIGMA rules.	cspec

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