BRCA1 NM_007294.3:c.4211T>G, Leu1404Arg

Variant summary: BRCA1 c.4211T>G (p.Leu1404Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251348 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4211T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Stoppa-Lyonnet_1997, Coupier_2004, Hasmad_2016, Bhaskaran_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence that a patient-derived lymphoblastoid cell line with the variant had a reduced capacity for DSB-repair, however it was not proven that the variant was responsible for this phenotype (e.g. Coupier_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1404 of the BRCA1 protein (p.Leu1404Arg). This variant is present in population databases (rs80356916, gnomAD 0.006%). This missense change has been observed in individual(s) with personal and family histories of breast and/or ovarian cancer (PMID: 9150149, 28692638, 35918668). ClinVar contains an entry for this variant (Variation ID: 491071). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14647443). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.