Variant classification summary

NM_000059.4:c.8168A>C

BRCA2 · NP_000050.3:p.(Asp2723Ala) · NM_000059.4

GRCh37: chr13:32937507 A>C · GRCh38: chr13:32363370 A>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Pathogenic

PS3 PP3 PP5

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Asp2723Ala)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8168A>C (p.Asp2723Ala; p.D2723A) variant has been reported in ClinVar as pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel and is listed by OncoKB as likely oncogenic.

2

This variant is present at very low frequency in population databases, with 1/251098 alleles in gnomAD v2.1 and 6/1614162 alleles in gnomAD v4.1, which is too low to support benign frequency criteria but means PM2 is not met because the variant is not absent from controls.

3

Calibrated BRCA2 functional evidence supports a damaging effect, and the ENIGMA curated functional table assigns PS3 at Strong strength for p.Asp2723Ala.

4

This missense change occurs within the BRCA2 DNA-binding domain, SpliceAI predicts no splice disruption with a max delta score of 0.00, and the computational profile supports PP3 rather than BP4.

Final determination: Likely Pathogenic based on 1 Strong pathogenic criterion and 2 Supporting pathogenic criteria (PS3_Strong + PP3_Supporting + PP5_Supporting) under ENIGMA Table 3.

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 splice-site, initiation-codon, or exon-deletion variant, so PVS1 does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously classified pathogenic or likely pathogenic variant producing the same amino acid change was identified. Other pathogenic missense changes have been reported at codon Asp2723, but different amino acid substitutions at the same codon do not satisfy PS1.	cspec vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	De novo evidence is not used for BRCA2 in this specification.	cspec
PS3	Met	Calibrated functional studies summarized by the ENIGMA BRCA2 specification show that this variant has damaging protein function consistent with pathogenic control variants, and the curated ENIGMA functional table assigns PS3 at Strong strength.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No qualifying variant-specific case-control study or odds ratio meeting ENIGMA PS4 thresholds was identified. The available structured BRCA2 supplementary datasets reviewed here did not provide a variant-specific PS4 assignment for this variant.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	PM1 is not applied in the BRCA2 ENIGMA specification.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/251098 alleles (AF 3.98e-06) and in gnomAD v4.1 at 6/1614162 alleles (AF 3.72e-06), so the ENIGMA requirement for absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a BRCA2-related Fanconi anemia phenotype, so PM3 could not be assessed.	cspec
PM4	N/A	PM4 is not applied in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	In this BRCA2 specification, PM5 is defined for protein-truncating variants in eligible exons and does not apply to this missense substitution.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo evidence is not used for BRCA2 in this specification.	cspec
PP1	Not assessed	No quantitative co-segregation likelihood ratio was identified, so PP1 could not be assessed.	cspec vcep_pmid_17924331_easton_2007_ajhg
PP2	N/A	PP2 is not applied in the BRCA2 ENIGMA specification.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain (aa 2481-3186), and the BayesDel no-AF score is 0.575545, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts no splice effect (max delta score 0.00), so the supporting computational evidence is for protein impact rather than splicing.	cspec spliceai
PP4	Not met	Variant-specific clinical-history evidence falls in the neutral zone. The BRCA2 clinical-history likelihood ratio is 1.329 with 2 probands, which is below the ENIGMA PP4 threshold of 2.08 and above the BP5 threshold range, so PP4 is not met.	cspec 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.	cspec clinvar
BA1	Not met	The population frequency is far below the ENIGMA BA1 threshold. In gnomAD v4.1 the highest filter allele frequency is 1.83e-06, which is below the BA1 cutoff of 0.001, so BA1 is not met.	cspec gnomad_v4 gnomad_v2
BS1	Not met	The population frequency does not reach the ENIGMA BS1 threshold. In gnomAD v4.1 the highest filter allele frequency is 1.83e-06, which is below the BS1_Supporting cutoff of 2.0e-05 and below the BS1 cutoff of 1.0e-04.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No proband-level evidence was identified to assign BS2 points under the BRCA2 Fanconi anemia framework, so BS2 could not be assessed.	cspec
BS3	Not met	Available functional evidence does not support a benign effect. The curated ENIGMA functional table assigns PS3 Strong rather than BS3 for this variant.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio was identified, so BS4 could not be assessed.	cspec vcep_pmid_17924331_easton_2007_ajhg
BP1	Not met	This missense variant is located within the BRCA2 DNA-binding domain, whereas BRCA2 BP1_Strong is reserved for missense or silent variants outside a clinically important functional domain with no splice effect. Although SpliceAI is 0.00, the domain requirement for BP1 is not met.	cspec spliceai
BP2	N/A	BP2 is not applied in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	BP3 is not applied in the BRCA2 ENIGMA specification.	cspec
BP4	Not met	Although SpliceAI predicts no splice effect (max delta score 0.00), BP4 is not met because this missense variant is in a clinically important functional domain and the BayesDel no-AF score is 0.575545, which is above the ENIGMA benign threshold of 0.18 rather than at or below it.	cspec spliceai
BP5	Not met	Variant-specific clinical-history evidence does not support a benign multifactorial signal. The BRCA2 clinical-history likelihood ratio is 1.329 with 2 probands, which is above the BP5 threshold of 0.48, so BP5 is not met.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not applied in the BRCA2 ENIGMA specification.	cspec
BP7	N/A	BP7 is intended for silent or intronic variants and for specific RNA-only benign contexts. This is a missense variant in a clinically important functional domain with damaging protein-function evidence, so BP7 does not apply.	cspec vcep_specifications_table9_v1_2_2024_11_18

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