NM_000059.4:c.7057G>C

BRCA2 · NP_000050.3:p.(Gly2353Arg) · NM_000059.4

GRCh37: chr13:32929047 G>C · GRCh38: chr13:32354910 G>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gly2353Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.7057G>C (p.Gly2353Arg) variant has been reported in ClinVar, where the aggregate record includes an ENIGMA expert panel Benign classification.

This variant is present in gnomAD, with grpmax filter allele frequencies of 2.859e-05 in v2.1 and 8.841e-05 in v4.1, which are above the ENIGMA BS1_Supporting threshold of 0.00002 and do not reach the BS1 Strong threshold of 0.0001.

In a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, including observed complementation and an HDR score of 82, and ENIGMA Table 9 assigns BS3 Strong.

Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a max delta score of 0.01, BayesDel no-AF is -0.110167, and codon 2353 lies outside the BRCA2 ENIGMA clinically important missense domains, supporting BP1 rather than PP3.

Final determination: Benign classification is supported because two strong benign criteria are met (BS3 and BP1), which satisfies the ENIGMA Table 3 benign 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	N/A	This missense variant does not fall within the BRCA2 null-variant or canonical splice-site categories used for PVS1, and SpliceAI predicts no significant splice impact (max delta score 0.01).	pvs1_gene_context pvs1_variant_assessment spliceai cspec
PS1	Not assessed	No evidence was identified showing that this amino acid change is the same protein consequence as a previously established pathogenic BRCA2 variant acting through the protein rather than splicing.	clinvar cspec
PS2	N/A	The BRCA2 ENIGMA specification does not use PS2 for this gene-specific framework.	cspec
PS3	Not met	Available functional evidence does not support a damaging effect. In a calibrated BRCA2 functional dataset, this variant showed protein function similar to benign control variants, so PS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
PS4	Not met	Available data do not show statistically significant enrichment in affected individuals at the ENIGMA PS4 threshold. No case-control evidence meeting the required significance standard was identified, and the available multifactorial dataset shows a case-control likelihood ratio of 1.88 rather than strong case enrichment.	vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 cspec
PM1	N/A	PM1 is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PM2	Not met	This variant is present in population databases and therefore does not meet ENIGMA PM2, which requires absence from controls. In gnomAD v2.1 the variant has AF 4.78332e-05 with grpmax FAF 2.859e-05, and in gnomAD v4.1 it has AF 7.74713e-05 with grpmax FAF 8.841e-05.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia, so PM3 could not be applied.	cspec
PM4	N/A	PM4 is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PM5	N/A	In the BRCA2 ENIGMA specification, PM5 is used for protein-truncating variants in eligible exons rather than for this missense substitution.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The BRCA2 ENIGMA specification does not use PM6 for this gene-specific framework.	cspec
PP1	Not met	Available family data do not support co-segregation with disease. The reviewed multifactorial dataset shows a segregation likelihood ratio of 0.345, which is below the PP1 threshold of 2.08 and instead supports BS4.	vcep_humu_40_1557_s001 cspec
PP2	N/A	PP2 is not used in the BRCA2 ENIGMA specification for this framework.	cspec
PP3	Not met	Computational evidence does not support a damaging effect. This residue lies outside the BRCA2 ENIGMA missense functional domains, BayesDel no-AF is -0.110167 which is below the PP3 threshold of 0.30, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, below the PP3 splice threshold of 0.2.	bayesdel spliceai cspec
PP4	Not assessed	No approved BRCA2 clinical-history likelihood-ratio result meeting ENIGMA PP4 thresholds was identified for this exact variant in the reviewed clinical-history table.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	N/A	PP5 is not used in current ACMG/AMP interpretation under this framework.	cspec
BA1	Not met	The population frequency does not reach the ENIGMA BA1 stand-alone benign threshold. The highest observed grpmax FAF is 8.841e-05 in gnomAD v4.1, which is below the BA1 threshold of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Met	This variant meets ENIGMA BS1_Supporting because the filter allele frequency is above 0.00002 and not above 0.0001. The grpmax FAF is 2.859e-05 in gnomAD v2.1 and 8.841e-05 in gnomAD v4.1, both within the BS1_Supporting range.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No data were identified showing this variant in sufficient individuals without features of BRCA2-related Fanconi anemia to apply BS2.	cspec
BS3	Met	In a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, with complementation observed and an HDR score of 82. ENIGMA Table 9 assigns BS3 Strong for this variant.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 cspec
BS4	Met	Available segregation evidence supports lack of segregation with disease. The segregation likelihood ratio is 0.345, which is below the ENIGMA BS4_Supporting threshold of 0.48.	vcep_humu_40_1557_s001 cspec
BP1	Met	This missense variant is outside the BRCA2 ENIGMA clinically important missense domains and has no predicted splice impact. Residue 2353 lies outside the PALB2 binding domain (aa 10-40) and DNA-binding region (aa 2481-3186), and SpliceAI is 0.01, below the no-splicing-impact threshold of 0.1, so BP1_Strong is met.	spliceai cspec
BP2	N/A	BP2 is not used in the BRCA2 ENIGMA specification for this framework.	cspec
BP3	N/A	BP3 is not used in the BRCA2 ENIGMA specification for this framework.	cspec
BP4	N/A	BP4 is not the applicable benign computational criterion for this variant under the BRCA2 ENIGMA framework. For missense variants outside the defined functional domains with no splice impact, the specification directs use of BP1 rather than BP4.	bayesdel spliceai cspec
BP5	Not assessed	No approved BRCA2 clinical-history likelihood-ratio result meeting ENIGMA BP5 thresholds was identified for this exact variant in the reviewed clinical-history table.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Benign.	cspec clinvar
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a silent or intronic variant in the BP7 evidence framework.	cspec spliceai

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