Submissions for variant NM_002878.4(RAD51D):c.607G>A (p.Val203Met)

gnomAD frequency: 0.00001  dbSNP: rs730881947

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160949	SCV000211656	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals undergoing multigene hereditary cancer panel testing (PMID: 27720647); This variant is associated with the following publications: (PMID: 14704354, 16717288, 21111057, 27720647)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545735	SCV000651763	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 203 of the RAD51D protein (p.Val203Met). This variant is present in population databases (rs730881947, gnomAD 0.007%). This missense change has been observed in individual(s) with hereditary cancer (PMID: 27720647). ClinVar contains an entry for this variant (Variation ID: 182860). 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.
Ambry Genetics	RCV000570494	SCV000667143	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-28	criteria provided, single submitter	clinical testing	The p.V203M variant (also known as c.607G>A), located in coding exon 7 of the RAD51D gene, results from a G to A substitution at nucleotide position 607. The valine at codon 203 is replaced by methionine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000570494	SCV000686473	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 203 of the RAD51D protein, near the Walker B motif in the ATPase domain (PMID: 14704354). 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. A functional study has reported that a different missense variant at this codon, p.Val203Asp, failed to complement MMC sensitivity of rad51d knockout hamster CHO cells and disrupted XRCC2 interaction in a yeast assay (PMID: 16717288). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251406 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.
Baylor Genetics	RCV000545735	SCV004200415	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160949	SCV004220181	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/251406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals who were part of a multigene hereditary cancel panel testing (PMID:27720647 (2016)). 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV003482135	SCV004228105	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000570494	SCV005415603	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-22	criteria provided, single submitter	clinical testing	The missense variant NM_002878.4(RAD51D):c.607G>A (p.Val203Met) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val203Met variant is observed in 1/16,252 (0.0062%) alleles from individuals of gnomAD African background in gnomAD. The p.Val203Met variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between valine and methionine, which is not likely to impact secondary protein structure as these residues share similar properties. 3 variants within 6 amino acid positions of the variant p.Val203Met have been shown to be pathogenic, while none have been shown to be benign. For these reasons, this variant has been classified as Uncertain Significance
Fulgent Genetics, Fulgent Genetics	RCV000545735	SCV005640005	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-05-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000545735	SCV005897621	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-12-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003422053	SCV004117080	uncertain significance	RAD51D-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The RAD51D c.607G>A variant is predicted to result in the amino acid substitution p.Val203Met. This variant was documented in at least one individual undergoing hereditary cancer testing; however, clinical or functional information was not provided (Table S3, Mu et al. 2016. PubMed ID: 27720647). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-33430533-C-T) and has been documented in ClinVar as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/182860/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.