Submissions for variant NM_002878.4(RAD51D):c.34C>G (p.Leu12Val)

gnomAD frequency: 0.00001  dbSNP: rs773065220

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544100	SCV000651737	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the RAD51D protein (p.Leu12Val). This variant is present in population databases (rs773065220, gnomAD 0.002%). 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: 472603). 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. 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	RCV000570834	SCV000667140	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-26	criteria provided, single submitter	clinical testing	The p.L12V variant (also known as c.34C>G), located in coding exon 1 of the RAD51D gene, results from a C to G substitution at nucleotide position 34. The leucine at codon 12 is replaced by valine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000570834	SCV001346389	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 12 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). 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 2/247698 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194375	SCV001363865	uncertain significance	not specified	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.34C>G (p.Leu12Val) results in a 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 8.2e-06 in 242656 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.34C>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
GeneDx	RCV002508227	SCV002817890	uncertain significance	not provided	2022-06-28	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 the germline of an individual with myeloid sarcoma; however, this individual also had a likely pathogenic variant in the EGFR gene (Walker et al., 2022); This variant is associated with the following publications: (PMID: 21111057, 35573754)
Baylor Genetics	RCV000544100	SCV005054012	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-10	criteria provided, single submitter	clinical testing