Submissions for variant NM_002878.4(RAD51D):c.802T>A (p.Trp268Arg)

dbSNP: rs755965977

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216827	SCV000278522	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.W268R variant (also known as c.802T>A), located in coding exon 9 of the RAD51D gene, results from a T to A substitution at nucleotide position 802. The tryptophan at codon 268 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000480783	SCV000566432	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532411	SCV000651782	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 268 of the RAD51D protein (p.Trp268Arg). This variant is present in population databases (rs755965977, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 234037). 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 RAD51D protein function with a positive predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000216827	SCV000686489	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with arginine at codon 268 of the RAD51D protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251430 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480783	SCV001134806	uncertain significance	not provided	2024-11-22	criteria provided, single submitter	clinical testing	The RAD51D c.802T>A (p.Trp268Arg) variant has not been reported in individuals with RAD51D-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV001818543	SCV002066826	uncertain significance	not specified	2021-01-25	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RAD51D gene demonstrated a sequence change, c.802T>A, in exon 9 that results in an amino acid change, p.Trp268Arg. This sequence change does not appear to have been previously described in patients with RAD51D-related disorders and has been described in the gnomAD database in just one individual (population frequency of 0.003% in the Latino/Admixed American subpopulation) (dbSNP rs755965977). The p.Trp268Arg change affects a highly conserved amino acid residue located in a domain of the RAD51D protein that is known to be functional. The p.Trp268Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) however this information does not predict clinical significance on its own. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Trp268Arg change remains unknown at this time.
Baylor Genetics	RCV000532411	SCV004200377	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-08-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000532411	SCV005639997	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-06-16	criteria provided, single submitter	clinical testing