Variant classification summary

NM_000059.4:c.8149G>T

BRCA2 · NP_000050.3:p.(Ala2717Ser) · NM_000059.4

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

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

BA1 BS1 BS3 BP6

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ala2717Ser)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been observed in somatic cancers in COSMIC (COSV66460731, n=3) and has also been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as benign.

2

This variant is common in population databases, with gnomAD v2.1 group-maximum filter allele frequency 0.00162114 and gnomAD v4.1 group-maximum filter allele frequency 0.00163682, both above the ENIGMA BA1 threshold of 0.001.

3

Calibrated BRCA2 functional evidence supports a benign effect: ENIGMA Table 9 assigns BS3 Strong based on three studies showing function similar to benign controls, with no aberrant RNA result listed.

4

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.03, which argues against splice disruption.

Final determination: BA1 alone meets the ENIGMA BRCA1/2 Table 3 benign classification rule; the additional benign evidence codes BS1, BS3, and BP6 are concordant with a benign classification.

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 variant, not a nonsense, frameshift, canonical ±1,2 splice, initiation codon, or deletion variant, and no damaging RNA-only result was identified. The ENIGMA BRCA2 PVS1 framework therefore does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No established pathogenic or likely pathogenic comparison variant producing the same amino acid change or the same proven splice effect was identified here, so PS1 was not assessed.	cspec
PS2	N/A	The ENIGMA BRCA2 specification does not apply PS2 in this framework.	cspec
PS3	Not met	Available calibrated functional evidence does not support a damaging effect. ENIGMA Table 9 lists this variant under BS3 Strong, with three studies showing protein function similar to benign controls and no aberrant RNA result, so PS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not assessed	This variant has been reported in affected individuals, but no case-control analysis with p-value ≤0.05 and odds ratio ≥4 was established here, so PS4 was not assessed.	cspec clinvar
PM1	N/A	The ENIGMA BRCA2 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 allele frequency is 0.00111433 (315/282680) and in gnomAD v4.1 it is 0.00139272 (2248/1614110), so the ENIGMA PM2 absence criterion is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	The ENIGMA BRCA2 specification marks PM4 as not applicable in this framework.	cspec
PM5	N/A	The BRCA2 ENIGMA PM5 rule in this framework is for protein-truncating variants in eligible exons. This missense variant does not meet that use case, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The ENIGMA BRCA2 specification marks PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No quantitative segregation likelihood ratio meeting ENIGMA thresholds was identified, so PP1 was not assessed.	cspec
PP2	N/A	The ENIGMA BRCA2 specification marks PP2 as not applicable in this framework.	cspec
PP3	Not assessed	SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.03, which is below the PP3 splice threshold of 0.2. However, ENIGMA PP3 for an in-domain missense variant also requires a BayesDel no-AF score of at least 0.30, and that protein-prediction value was not established here, so PP3 was not assessed.	spliceai cspec
PP4	Not assessed	No qualifying BRCA2 clinical-history likelihood ratio was identified for this variant, so PP4 was not assessed.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
PP5	N/A	The ENIGMA BRCA2 specification marks PP5 as not applicable in this framework.	cspec
BA1	Met	This variant is common in population databases. The gnomAD v2.1 group-maximum filter allele frequency is 0.00162114 and the gnomAD v4.1 group-maximum filter allele frequency is 0.00163682, both above the ENIGMA BA1 threshold of 0.001, so BA1 is met.	gnomad_v2 gnomad_v4 cspec
BS1	Met	This variant exceeds the ENIGMA BS1 threshold for benign population frequency. The gnomAD v2.1 group-maximum filter allele frequency is 0.00162114 and the gnomAD v4.1 group-maximum filter allele frequency is 0.00163682, both above the BS1 strong threshold of 0.0001.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying observations in individuals lacking Fanconi anemia features were identified under the ENIGMA BRCA2 BS2 point-based framework, so BS2 was not assessed.	cspec
BS3	Met	ENIGMA Table 9 assigns BS3 Strong to this variant. Three calibrated studies reported protein function similar to benign control variants, and the listed RNA result showed no aberration, which supports a benign functional interpretation.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio meeting ENIGMA thresholds was established here, so BS4 was not assessed.	cspec
BP1	Not met	This missense variant lies within the BRCA2 DNA-binding region (amino acids 2481-3186). ENIGMA BP1_Strong applies only to missense or in-frame variants outside clinically important domains with no splice impact predicted, so BP1 is not met.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	The ENIGMA BRCA2 specification marks BP2 as not applicable in this framework.	cspec
BP3	N/A	The ENIGMA BRCA2 specification marks BP3 as not applicable in this framework.	cspec
BP4	Not assessed	SpliceAI predicts no significant splice effect, with a maximum delta score of 0.03, which is below the BP4 splice threshold of 0.1. However, ENIGMA BP4 for a missense variant inside a clinically important domain also requires a BayesDel no-AF score of 0.18 or less, and that protein-prediction value was not established here, so BP4 was not assessed.	spliceai cspec
BP5	Not assessed	No qualifying BRCA2 clinical-history likelihood ratio at or below the ENIGMA BP5 thresholds was identified for this variant, so BP5 was not assessed.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	This is a missense variant rather than a silent or qualifying intronic variant, so the ENIGMA BP7 rule does not apply.	cspec spliceai

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