Submissions for variant NM_002878.4(RAD51D):c.824G>A (p.Arg275Gln)

gnomAD frequency: 0.00001  dbSNP: rs368914740

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165258	SCV000215974	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	The p.R275Q variant (also known as c.824G>A), located in coding exon 9 of the RAD51D gene, results from a G to A substitution at nucleotide position 824. The arginine at codon 275 is replaced by glutamine, an amino acid with highly similar 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	RCV000235620	SCV000293084	uncertain significance	not provided	2024-09-24	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; Identified in an individual undergoing multi-gene hereditary cancer panel testing, who also carried a pathogenic variant in CHEK2 (PMID: 35534704); This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148, 35534704)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470966	SCV000551324	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 275 of the RAD51D protein (p.Arg275Gln). This variant is present in population databases (rs368914740, gnomAD 0.0009%). 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: 185774). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165258	SCV000686491	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 275 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 RAD51D-related disorders in the literature. This variant has been identified in 1/251444 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.
Genetics and Molecular Pathology, SA Pathology	RCV000470966	SCV002556525	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2021-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000470966	SCV005054016	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751308	SCV005344403	uncertain significance	RAD51D-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The RAD51D c.824G>A variant is predicted to result in the amino acid substitution p.Arg275Gln. This variant has been reported in a Turkish individual with breast cancer and in a male with prostate cancer of African ancestry (Table S6. Akcay et al. 2020. PubMed ID: 32658311; Table S2. Matejcic et al. 2020. PubMed ID: 32832836). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185774/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.