Variant classification summary

NM_000059.3:c.8149G>T

BRCA2 · NP_000050.2:p.(Ala2717Ser) · NM_000059.3

GRCh37: chr13:32937488 G>T · GRCh38: chr13:32363351 G>T

Gene: BRCA2 Transcript: NM_000059.3

Final call

Benign

BA1 BS3 BP6

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Ala2717Ser)

gnomAD AF

0.001392717968416031 (v4.1)

ClinVar

Benign

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been reported in ClinVar as Benign with expert panel review, and curated cancer resources did not identify it as a statistically significant hotspot while OncoKB describes it as likely neutral.

2

This variant is present in population databases at a frequency above the BRCA2 ENIGMA BA1 threshold, with grpmax filtering allele frequency 0.00162114 in gnomAD v2.1 and 0.00163682 in gnomAD v4.1, supporting a benign population interpretation.

3

In curated BRCA2 functional studies, this variant showed protein function similar to benign control variants, and associated RNA data showed no aberrant splicing, supporting BS3_Strong.

4

Computational evidence does not support a damaging interpretation under the BRCA2 ENIGMA rules: the BayesDel no-AF score is -0.0816274, REVEL is 0.535, and no SpliceAI score demonstrating splice impact was identified, so PP3 is not met and BP4 could not be fully applied.

Final determination: Stand-alone benign population evidence (BA1) is sufficient for a Benign classification under the ENIGMA BRCA1/BRCA2 Table 3 combining rules; BS3 and BP6 provide additional concordant benign support.

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	This is a missense substitution, not a nonsense, frameshift, or canonical +/-1,2 splice-site variant, and no RNA evidence was identified showing a null transcript effect. Under the BRCA2 ENIGMA framework, PVS1 is therefore not applicable.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No evidence was identified that this variant produces the same amino-acid change or the same predicted splice effect as a previously classified pathogenic or likely pathogenic BRCA2 variant. PS1 is not met based on the available data.	cspec clinvar
PS2	N/A	The BRCA2 ENIGMA specification marks PS2 as not applicable in this framework.	cspec
PS3	Not met	Published functional data curated by the BRCA2 ENIGMA expert framework showed protein function similar to benign control variants rather than a damaging effect, so PS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not met	No case-control evidence was identified showing that this variant is significantly enriched in affected individuals, and the variant is also observed at a population frequency that is too high to support PS4. Available evidence does not support increased prevalence in affected individuals.	cspec gnomad_v2 gnomad_v4 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	The BRCA2 ENIGMA specification marks PM1 as not applicable in this framework.	cspec
PM2	Not met	This variant is not absent from population databases. In gnomAD v2.1 the overall allele frequency is 0.11143% with grpmax FAF 0.00162114, and in gnomAD v4.1 the overall allele frequency is 0.13927% with grpmax FAF 0.00163682, so the ENIGMA PM2 absence criterion is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia. PM3 was not assessed from the available data.	cspec
PM4	N/A	The BRCA2 ENIGMA specification marks PM4 as not applicable in this framework.	cspec
PM5	N/A	For BRCA2 in this ENIGMA framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. Because this variant is a missense substitution, PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	The BRCA2 ENIGMA specification marks PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No quantitative co-segregation evidence was identified for this variant in affected relatives. PP1 was not assessed from the available data.	cspec clinvar
PP2	N/A	The BRCA2 ENIGMA specification marks PP2 as not applicable in this framework.	cspec
PP3	Not met	This missense variant lies in the BRCA2 DNA-binding region, but the available computational evidence does not meet the ENIGMA PP3 threshold. The BayesDel no-AF score is -0.0816274, which is below the required threshold of 0.30, and no SpliceAI result showing a score of at least 0.2 was identified.	cspec bayesdel spliceai revel
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA thresholds was identified for this variant, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	The BRCA2 ENIGMA specification marks PP5 as not applicable in this framework.	cspec
BA1	Met	This variant exceeds the BRCA2 ENIGMA BA1 population threshold. The grpmax filtering allele frequency is 0.00162114 in gnomAD v2.1 and 0.00163682 in gnomAD v4.1, both above the BA1 threshold of 0.001 in non-founder populations.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Population frequency evidence was captured under BA1. Although the variant also exceeds the BS1 thresholds, BS1 was not separately applied to avoid double-counting the same population data.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA point-based BS2 framework. BS2 was not assessed.	cspec
BS3	Met	In the BRCA2 ENIGMA curated functional dataset, this variant was assigned BS3 Strong. Published calibrated functional studies showed protein function similar to benign control variants, and RNA data in the same curation entry showed no aberrant splicing.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant in affected relatives. BS4 was not assessed from the available data.	cspec vcep_supplementarytables_v1_2_2024_11_18 clinvar
BP1	Not met	This missense variant is located at codon 2717 within the BRCA2 DNA-binding region defined by ENIGMA as a clinically important functional domain (amino acids 2481-3186). BP1, which is reserved for variants outside these domains without predicted splice impact, is not met.	cspec
BP2	N/A	The BRCA2 ENIGMA specification marks BP2 as not applicable in this framework.	cspec
BP3	N/A	The BRCA2 ENIGMA specification marks BP3 as not applicable in this framework.	cspec
BP4	Not met	The BayesDel no-AF score is -0.0816274, which is consistent with the benign side of the BRCA2 ENIGMA threshold, but BP4 for a missense variant in a clinically important domain also requires SpliceAI less than or equal to 0.1. Because no SpliceAI result was identified, BP4 is not met from the available data.	cspec bayesdel spliceai
BP5	Not assessed	No variant-specific clinical-history likelihood ratio in the benign direction was identified for this variant, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	Not assessed	RNA evidence curated for this variant reported no aberrant splicing, but the available materials did not provide a direct ENIGMA BP7 assignment for this missense variant. BP7 was therefore not separately assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18

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