ClinVar Genomic variation as it relates to human health

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 119 of the RAD51D protein (p.Cys119Tyr). This variant is present in population databases (rs759730492, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary breast cancer (PMID: 31206626). ClinVar contains an entry for this variant (Variation ID: 234195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function. 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.

The p.C119Y variant (also known as c.356G>A), located in coding exon 5 of the RAD51D gene, results from a G to A substitution at nucleotide position 356. The cysteine at codon 119 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces cysteine with tyrosine at codon 119 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Variant summary: RAD51D c.356G>A (p.Cys119Tyr) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251398 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.356G>A has been reported in the literature in at-least one individual affected with BRCA-mutation-negative hereditary breast cancer without evidence for causality (Weitzel_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with other pathogenic variant have been reported (MLH1 c.677+1G>T), providing supporting evidence for a benign role (Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and/or family history of breast and/or ovarian cancer (Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148, 31206626)

The frequency of this variant in the general population, 0.00017 (6/34592 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 31206626 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.