NM_000059.3:c.8375T>C

BRCA2 · NP_000050.2:p.(Leu2792Pro) · NM_000059.3

GRCh37: chr13:32944582 T>C · GRCh38: chr13:32370445 T>C

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.(Leu2792Pro)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.8375T>C (p.Leu2792Pro) variant has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA.

This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1613924 alleles; AF 6.19608e-07), supporting rarity but not strict absence across available population datasets.

In the ENIGMA BRCA2 curated functional dataset, two calibrated studies showed damaging protein function for this exact variant, and Table 9 assigns PS3 at strong strength.

In silico data support a damaging protein effect within the BRCA2 DNA-binding domain, with BayesDel 0.54225 and REVEL 0.931, while SpliceAI predicts no significant splice impact (max delta 0.03).

Final determination: Likely pathogenic classification is supported because one strong and two supporting pathogenic criteria are met (PS3_Strong, PP3_Supporting, and PP5_Supporting), satisfying the ENIGMA Table 3 likely pathogenic combining rule.

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, p.(Leu2792Pro), and does not fall into the BRCA2 null-variant or canonical splice categories used for PVS1. SpliceAI predicts no significant splice effect (max delta score 0.03), so available evidence does not support applying PVS1.	pvs1_variant_assessment spliceai cspec
PS1	Not met	No distinct previously classified pathogenic or likely pathogenic variant producing the same amino acid change was identified in the available ClinVar evidence, so PS1 is not established.	clinvar cspec
PS2	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
PS3	Met	In the ENIGMA BRCA2 functional assay table, this exact variant, c.8375T>C (p.Leu2792Pro), is reported by two calibrated studies to show damaging protein function, and the table assigns PS3 at strong strength.	vcep_specifications_table9_v1_2_2024_11_18 PMID:29884841 cspec
PS4	Not assessed	No case-control analysis or other evidence showing statistically significant enrichment in affected individuals was identified for this variant, and no exact-variant entry was identified in the reviewed BRCA2 multifactorial/posterior tables for PS4 use.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PM1	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1, but it is present in gnomAD v4.1 at 1/1613924 alleles (AF 6.19608e-07; highest population AF 8.47529e-07 in European non-Finnish). Available population data therefore support rarity, but do not establish the strict absence required for ENIGMA PM2.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with another BRCA2 pathogenic variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed.	cspec
PM4	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	In the BRCA2 ENIGMA specification, PM5 is defined here for protein-terminating variants in eligible exons. This missense variant does not meet that use case.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, and no exact-variant segregation likelihood ratio was identified in the reviewed BRCA2 multifactorial resources, so PP1 cannot be applied.	vcep_humu_40_1557_s001 cspec
PP2	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
PP3	Met	This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain defined by ENIGMA (amino acids 2481-3186). BayesDel is 0.54225, which is above the ENIGMA PP3 threshold of 0.30, and REVEL is also high at 0.931. SpliceAI predicts no significant splice effect (max delta 0.03), so the computational evidence supports a damaging protein effect rather than a splice mechanism.	cspec bayesdel revel spliceai vcep_appendices_v1_2_2024_11_18
PP4	Not assessed	No exact-variant personal or family-history likelihood ratio was identified in the reviewed BRCA2 clinical-history table, so PP4 cannot be applied from the available multifactorial clinical data.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	Available population data do not meet the ENIGMA BA1 threshold. The observed gnomAD v4.1 frequency is 6.19608e-07, which is far below the BA1 threshold of greater than 0.001.	gnomad_v4 cspec
BS1	Not met	Available population data do not meet the ENIGMA BS1 thresholds. The observed gnomAD v4.1 frequency is 6.19608e-07, which is below the supporting threshold of greater than 0.00002 and far below the strong threshold of greater than 0.0001.	gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that permits ENIGMA BS2 point assignment.	cspec
BS3	Not met	Available functional evidence does not support a benign effect. Instead, the ENIGMA BRCA2 functional assay table reports that two calibrated studies showed damaging protein function for this exact variant and assigns PS3_Strong.	vcep_specifications_table9_v1_2_2024_11_18 PMID:29884841 cspec
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, and no exact-variant segregation likelihood ratio was identified in the reviewed BRCA2 multifactorial resources, so BS4 cannot be applied.	vcep_humu_40_1557_s001 cspec
BP1	Not met	BP1_Strong is reserved for missense or silent variants outside clinically important BRCA2 domains with no predicted splice effect. This variant is within the BRCA2 DNA-binding domain, so BP1 is not met.	cspec spliceai
BP2	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
BP4	Not met	This variant is within the BRCA2 DNA-binding domain, but the computational results do not meet the benign thresholds. BayesDel is 0.54225, which is above the BP4 threshold of 0.18, although SpliceAI is low at 0.03. Available in silico evidence therefore does not support BP4.	cspec bayesdel spliceai
BP5	Not assessed	No exact-variant personal or family-history likelihood ratio was identified in the reviewed BRCA2 clinical-history table, so BP5 cannot be applied from the available multifactorial clinical data.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	This criterion is marked not applicable in the BRCA2 ENIGMA specification.	cspec
BP7	N/A	BP7 in this framework is for silent or qualifying intronic variants, and this is a missense variant within a clinically important BRCA2 domain.	cspec spliceai

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