Submissions for variant NM_002878.4(RAD51D):c.869G>A (p.Arg290Gln)

gnomAD frequency: 0.00001  dbSNP: rs773883374

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216468	SCV000275156	likely benign	Hereditary cancer-predisposing syndrome	2018-03-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230122	SCV000287727	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-14	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 290 of the RAD51D protein (p.Arg290Gln). This variant is present in population databases (rs773883374, gnomAD 0.01%). 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: 231338). 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 not expected to disrupt RAD51D protein function with a negative 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.
GeneDx	RCV000485412	SCV000568984	uncertain significance	not provided	2023-10-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer and also in an unaffected control (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 19327148, 21111057, 14704354)
Color Diagnostics, LLC DBA Color Health	RCV000216468	SCV000903446	likely benign	Hereditary cancer-predisposing syndrome	2015-12-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000216468	SCV002534862	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485412	SCV005623974	uncertain significance	not provided	2024-02-13	criteria provided, single submitter	clinical testing	The RAD51D c.869G>A (p.Arg290Gln) variant has been reported in the published literature as a somatic variant in tumor samples from individuals with ovarian cancer (PMID: 28852190 (2017)) and colorectal cancer (PMID: 32620917 (2020)). To the best of our knowledge, this variant has not been reported germline in individuals with RAD51D related cancers. The frequency of this variant in the general population, 0.000035 (4/113710 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.