Variant classification summary

NM_000059.3:c.8164A>G

BRCA2 · NP_000050.2:p.(Thr2722Ala) · NM_000059.3

GRCh37: chr13:32937503 A>G · GRCh38: chr13:32363366 A>G

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Pathogenic

PS3_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Thr2722Ala)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8164A>G (p.Thr2722Ala) variant has not been observed in COSMIC and has been reported in ClinVar as Likely Pathogenic, including expert-panel review by ClinGen ENIGMA BRCA1/2.

2

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), supporting that it is very rare in population databases.

3

In a calibrated BRCA2 functional study, this variant showed protein function similar to pathogenic control variants, and the ENIGMA BRCA2 functional table assigns PS3 at strong strength for p.Thr2722Ala.

4

This missense change lies within the BRCA2 DNA-binding domain, has a BayesDel no-AF score of 0.396861 above the ENIGMA PP3 threshold of 0.30, and has low predicted splice impact by SpliceAI (maximum delta score 0.01).

Final determination: Likely Pathogenic based on 1 Strong and 2 Supporting pathogenic criteria under the ENIGMA BRCA1/BRCA2 Table 3 combination rules.

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 variant, and available data do not show an RNA-only loss-of-function effect. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so available evidence does not support PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	No previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same predicted splice effect was identified in the available evidence, so PS1 is not met.	cspec
PS2	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
PS3	Met	In a calibrated BRCA2 functional dataset, this variant was reported to show protein function similar to pathogenic control variants, and the ENIGMA BRCA2 Table 9 assigns PS3 at strong strength for c.8164A>G (p.Thr2722Ala). This supports a damaging effect on protein function.	vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 cspec
PS4	Not assessed	Available evidence does not provide a case-control analysis or a quantitative demonstration that this variant is significantly enriched in affected individuals relative to controls, so PS4 cannot be assigned from the reviewed data.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
PM1	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), which is consistent with rarity. However, the ENIGMA BRCA2 PM2 rule is defined against absence in gnomAD v2.1 and v3.1 with adequate coverage, and a v3.1-specific assessment was not available here, so PM2 was not formally assigned.	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 phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	For BRCA2 in this specification, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison. Because this variant is a missense substitution, PM5 is not applicable.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so there is no quantitative likelihood ratio to support PP1.	cspec vcep_pmid_17924331_easton_2007_ajhg clinvar
PP2	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding domain and has a BayesDel no-AF score of 0.396861, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts low splice impact with a maximum delta score of 0.01, so the computational evidence supports a damaging protein effect rather than a splice effect.	cspec bayesdel spliceai
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the reviewed BRCA2 clinical-history resource, so PP4 was not assigned.	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 Likely pathogenic.	cspec clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (AF 6.19e-07), which is far below the ENIGMA BA1 threshold of filter allele frequency greater than 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not meet the ENIGMA BS1 thresholds. This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (AF 6.19e-07), which is far below the supporting threshold of filter allele frequency greater than 0.00002 and the strong threshold of greater than 0.0001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified to score this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA point-based BS2 framework, so BS2 was not assessed.	cspec
BS3	Not met	Available functional evidence does not support a benign effect. Instead, the calibrated ENIGMA BRCA2 functional table assigns PS3_Strong for this exact variant, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 cspec
BS4	Not assessed	No lack-of-segregation data or quantitative non-segregation likelihood ratio was identified for this variant, so BS4 was not assigned.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg
BP1	Not met	This missense variant is located within the BRCA2 DNA-binding domain, so it does not meet the ENIGMA BP1 rule, which is restricted to missense or similar variants outside clinically important functional domains with no predicted splice impact.	cspec spliceai
BP2	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
BP4	Not met	This variant does not meet the ENIGMA BP4 rule because it is a missense change in the BRCA2 DNA-binding domain and its BayesDel no-AF score is 0.396861, which is above the benign threshold of 0.18. SpliceAI predicts low splice impact (max delta score 0.01), but the protein-based computational evidence does not support a benign interpretation.	cspec bayesdel spliceai
BP5	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified in the reviewed BRCA2 clinical-history resource, so BP5 was not assigned.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not applicable in the BRCA2 ENIGMA specification.	cspec
BP7	Not met	This is a missense variant within a clinically important BRCA2 functional domain, and no benign RNA evidence was identified. Available functional evidence instead supports a damaging effect, so BP7 is not met.	cspec spliceai vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.