ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 29522266, 27616075)

Variant summary: RAD51D c.163C>T (p.Arg55Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251236 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.163C>T has been reported in the literature in individuals affected with Breast/Ovarian Cancer (Kraus_2016, Kwong_2020), however, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with another pathogenic variant has been seen in our laboratory (BRCA1 c.3598C>T, p.Q1200*), providing supporting evidence for a benign role. A minigene splicing assay spanning exon 2-9 has demonstrated that the variant does not significantly impact splicing as compared to the wild-type sequence, showing that 62% of the total transcripts produced were of full length compared to 73% seen with wild type (Bueno-Martinez_2021). Four ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.R55W variant (also known as c.163C>T), located in coding exon 3 of the RAD51D gene, results from a C to T substitution at nucleotide position 163. The arginine at codon 55 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has identified in multiple individuals diagnosed with breast cancer (Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102; Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358; Kwong A et al. J Mol Diagn, 2020 Apr;22:544-554). This amino acid position is highly 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.

a variant of uncertain significance was detected in the RAD51D gene (p.Arg55Trp).This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 55 of the RAD51D protein (p.Arg55Trp). This variant is present in population databases (rs775268017, gnomAD 0.003%). This amino acid position is mild conserved (PhyloP=3.9). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 230594). In addition, this alteration is predicted to be tolerated by in silico analysis. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 34200360). 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.

This missense variant replaces arginine with tryptophan at codon 55 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). A mini-gene splicing assay has shown this variant to affect splicing, resulting in the production of multiple different transcripts with the normal, full-length transcript being the most abundant transcript (PMID: 34200360). This variant has been reported in an individual affected with breast cancer (PMID: 27616075). This variant has been identified in 2/251236 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.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 55 of the RAD51D protein (p.Arg55Trp). This variant is present in population databases (rs775268017, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 230594). 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 expected to disrupt RAD51D protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 34200360; Invitae). 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.

RAD51D: PM2, BP1, BP4