Submissions for variant NM_002878.4(RAD51D):c.101C>T (p.Ala34Val)

gnomAD frequency: 0.00004  dbSNP: rs876658968

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214363	SCV000274863	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The p.A34V variant (also known as c.101C>T), located in coding exon 2 of the RAD51D gene, results from a C to T substitution at nucleotide position 101. The alanine at codon 34 is replaced by valine, an amino acid with similar properties. This alteration was identified in a cohort of 181 African American women with breast cancer, and was found not to affect protein-protein interactions via yeast 2-hybrid assay (Ding YC et al. Fam. Cancer, 2018 04;17:187-195). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001580475	SCV000698089	uncertain significance	not specified	2021-08-19	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.101C>T (p.Ala34Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.101C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Ding_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Ding_2017) for XRCC2-RAD51D protein-protein interactions assessed by a yeast two hybrid system. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000649678	SCV000771510	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the RAD51D protein (p.Ala34Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 28864920). ClinVar contains an entry for this variant (Variation ID: 231115). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RAD51D function (PMID: 28864920). 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	RCV000214363	SCV000913999	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 34 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 functional study has shown the mutant protein to retain the ability to bind XRCC2 normally in yeast two-hybrid assay (PMID: 28864920). This variant has been reported in an individual affected with breast cancer (PMID: 28864920). This variant has been identified in 1/251456 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.
GeneDx	RCV000588755	SCV001765728	uncertain significance	not provided	2024-11-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect on interaction with XRCC2 (PMID: 28864920); Observed in individuals with breast cancer (PMID: 28864920); This variant is associated with the following publications: (PMID: 28864920, 21111057)
Baylor Genetics	RCV000649678	SCV004200379	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-08-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588755	SCV004220161	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251456 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, a yeast two hybrid study has shown that this variant does not significantly affect protein binding with the XRCC2 protein (PMID: 28864920 (2018)). Further studies are required to determine the global effect of this variant on RAD51D protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV004751384	SCV005361180	uncertain significance	RAD51D-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The RAD51D c.101C>T variant is predicted to result in the amino acid substitution p.Ala34Val. This variant was reported in an individual with breast cancer (Ding et al. 2018. PubMed ID: 28864920). Functional studies have shown that this variant does not significantly affect RAD51D protein function (Table 2, Ding et al. 2018. PubMed ID: 28864920). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/231115/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.