ClinVar

Description

Variant summary: BRCA2 c.440A>T (p.Gln147Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245932 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.440A>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reports experimental evidence that this variant might affect mRNA splicing via a combined effect of Exon Splicing Enhancer disruption and Exonic Splicing Silencers creation in a large-scale minigene system (Fraile-Bethencourt_2019). However, such effect is less notable when compared with WT. The following publications have been ascertained in the context of this evaluation (PMID: 30883759, 25186627). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.