BRCA2 NM_000059.4:c.7057G>C, Gly2353Arg

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000782

Variant summary: The BRCA2 c.7057G>C (p.Gly2353Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 8/122392 control chromosomes at a frequency of 0.0000654, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was found in HBOC spectrum patients however, without strong evidence for pathogenicity. In fact, the variant was observed in several patients to co-occur with (potentially) pathogenic BRCA1 and BRCA2 variants such as BRCA1 c.3193_3194insG (p.Asp1065?fs); BRCA2 c.4478_4481delAAAG (p.Glu1493_Ser1494?fs); BRCA2 c.476-2A>G; BRCA1 c.IVS5+1G>A (c.212+1G>A) BRCA1 c.3612delA (p.Ala1206ProfsX4), BRCA1 c.2346dupT indicating neutrality. Furthermore, Lindor_HM_2012 reviewed a multifactorial probability based model and calculated, odds in favor of causality was 0.03 and posterior probability of being deleterious 6.12104 and classified the variant as IARC Class I (Neutral) variant. Additionally, Alsop_2012 reports LOH of the variant within a breast tumor. Moreover, several clinical diagnostic laboratories classify variant as Benign/Likely benign via ClinVar. Considering all evidence, the variant was classified as Likely Benign.