Submissions for variant NM_058216.3(RAD51C):c.28A>T (p.Met10Leu)

gnomAD frequency: 0.00001  dbSNP: rs1452865935

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561155	SCV000667098	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.M10L variant (also known as c.28A>T), located in coding exon 1 of the RAD51C gene, results from an A to T substitution at nucleotide position 28. The methionine at codon 10 is replaced by leucine, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317287	SCV000699801	uncertain significance	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.28A>T (p.Met10Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.28A>T has been reported in the literature as a VUS in a setting of multigene panel testing in an individual affected with breast cancer, suspected of a hereditary cancer syndrome (Bishop_2020). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32866190). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703119	SCV000832001	uncertain significance	Fanconi anemia complementation group O	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 10 of the RAD51C protein (p.Met10Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 482159). 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.
Color Diagnostics, LLC DBA Color Health	RCV000561155	SCV000913013	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 10 of the RAD51C 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 1/31382 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	RCV003465210	SCV004209756	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478239	SCV004220139	uncertain significance	not provided	2023-01-09	criteria provided, single submitter	clinical testing	The variant has not been reported in individuals with RAD51C-related conditions in the published literature. The frequency of this variant in the general population, 0.000032 (1/31382 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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.