BRCA1 NM_007294.4:c.4327C>G, Arg1443Gly

Variant summary: BRCA1 c.4327C>G (p.Arg1443Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.4327C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (e.g. Ahmed_2012, Alsop_2012, Castilla_1994, Haffty_2009, Judkins_2005, Trujillano_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the BIC and UMD databases respectively (BRCA1 c.3G>T, p.Met1Ile; BRCA1 c.269_281del, p.Ile90SerfsX25), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Bouwman_2013, Carvalho_2007, Sy_2009, Woods_2016, Fernandes_2019). Nine clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3, likely benign, n=6, VUS, n=1). Based on the evidence outlined above, to reflect the emerging consensus towards a benign outcome, the variant was classified as benign.

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 = 2.23E-06

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.