NM_000059.3:c.7961T>C

BRCA2 · NP_000050.2:p.(Leu2654Pro) · NM_000059.3

GRCh37: chr13:32936815 T>C · GRCh38: chr13:32362678 T>C

Gene: BRCA2 Transcript: NM_000059.3

Final call

PP3_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Leu2654Pro)

gnomAD AF

1.8586600547932985e-06 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.7961T>C (p.Leu2654Pro) variant has been reported in ClinVar with an expert-panel classification of uncertain significance and mixed submitter assertions.

This variant is present at very low frequency in population databases, including 1/31,406 alleles in gnomAD v2.1 and 3/1,614,066 alleles in gnomAD v4.1, which argues against PM2 and does not reach BA1 or BS1 thresholds.

In the ENIGMA BRCA2 curated functional dataset, this variant has discordant calibrated assay results, so the available functional evidence does not support either PS3 or BS3.

Computational evidence supports a damaging protein effect because the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314702 above the PP3 threshold of 0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect with a max delta score of 0.02.

Final determination: With PP3_Supporting as the only met criterion and no benign or additional pathogenic criteria meeting an ENIGMA Table 3 combination for likely pathogenic, pathogenic, likely benign, or benign, the variant is classified as Uncertain Significance.

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	Not met	This variant is a missense substitution, not a nonsense, frameshift, or canonical ±1/2 splice-site variant, and no RNA evidence showing an abnormal loss-of-function transcript was identified. SpliceAI predicts no significant splice impact (max delta 0.02), so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No verified evidence was identified showing that this variant produces the same pathogenic amino-acid change or the same pathogenic splicing effect as a previously classified pathogenic or likely pathogenic BRCA2 variant, so PS1 was not assessed.	cspec
PS2	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PS3	Not met	In the ENIGMA BRCA2 functional table, this variant is summarized as having discordant results across two or more calibrated studies. One study reported a damaging effect and another placed the result between benign and pathogenic controls, so the available functional evidence does not support PS3.	vcep_specifications_table9_v1_2_2024_11_18 PMID:29884841
PS4	Not assessed	No case-control study, odds ratio, or quantitative enrichment data were identified showing this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed.	cspec clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework, even for missense variants in the DNA-binding domain.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/31,406 alleles (AF 3.1841e-05) and in gnomAD v4.1 at 3/1,614,066 alleles (AF 1.85866e-06), so PM2 is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec clinvar
PM4	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PM5	N/A	In the BRCA2 ENIGMA specification, PM5 is repurposed for protein-truncating variants in exons where a different proven pathogenic truncating variant has been observed. This variant is missense, so PM5 is not applicable.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	cspec clinvar
PP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding domain (aa 2481-3186). BayesDel no-AF is 0.314702, which is above the ENIGMA PP3 threshold of ≥0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect (max delta 0.02), supporting a damaging protein effect; therefore PP3 is met at supporting strength.	cspec bayesdel revel spliceai
PP4	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 1.4293 in 2 probands. This is below the ENIGMA PP4 supporting threshold of ≥2.08, so PP4 is not met.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
BA1	Not met	Available population data do not reach the BA1 threshold. In gnomAD v4.1, the highest available group maximum filter allele frequency is 4.43e-06, which is below the ENIGMA BA1 threshold of >0.001.	cspec gnomad_v4
BS1	Not met	Available population data do not reach the BS1 thresholds. In gnomAD v4.1, the highest available group maximum filter allele frequency is 4.43e-06, which is below the ENIGMA BS1 supporting threshold of >0.00002 and the strong threshold of >0.0001.	cspec gnomad_v4
BS2	Not assessed	No qualifying observations were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 scoring framework, so BS2 was not assessed.	cspec
BS3	Not met	In the ENIGMA BRCA2 functional table, this variant is summarized as having discordant results across calibrated studies rather than a consistent normal-function result. Because the curated table does not assign BS3, the available functional evidence does not support BS3.	vcep_specifications_table9_v1_2_2024_11_18 PMID:29884841
BS4	Not assessed	No quantitative non-segregation data were identified for this variant, so BS4 was not assessed.	cspec clinvar
BP1	Not met	BP1_Strong in the ENIGMA BRCA2 specification applies to missense variants outside clinically important domains with no predicted splice effect. This variant is in the BRCA2 DNA-binding domain, so BP1 is not met.	cspec spliceai
BP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
BP3	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
BP4	Not met	Although SpliceAI predicts no significant splice impact (max delta 0.02), this missense variant is in the BRCA2 DNA-binding domain and BayesDel no-AF is 0.314702, which is above the BP4 requirement of ≤0.18. REVEL is also high at 0.82. Therefore BP4 is not met.	cspec bayesdel revel spliceai
BP5	Not met	The BRCA2 clinical-history likelihood ratio for this variant is 1.4293 in 2 probands. This is above the ENIGMA BP5 supporting threshold of ≤0.48 and falls in the neutral zone, so BP5 is not met.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not used in the BRCA2 ENIGMA specification for this framework.	cspec
BP7	N/A	BP7 in this framework is for silent or specified intronic variants, and for RNA-only evidence under defined circumstances. This variant is a missense change in the BRCA2 DNA-binding domain, so BP7 is not applicable.	cspec spliceai

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