Submissions for variant NM_058216.3(RAD51C):c.563A>T (p.Lys188Met)

gnomAD frequency: 0.00001  dbSNP: rs587781680

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129840	SCV000184656	likely benign	Hereditary cancer-predisposing syndrome	2019-04-29	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	RCV000648258	SCV000770072	uncertain significance	Fanconi anemia complementation group O	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 188 of the RAD51C protein (p.Lys188Met). This variant is present in population databases (rs587781680, gnomAD 0.02%). 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: 141353). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000129840	SCV000909447	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with methionine at codon 188 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 7/282878 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	RCV000648258	SCV002030086	uncertain significance	Fanconi anemia complementation group O	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV001818306	SCV002070112	uncertain significance	not specified	2020-02-11	criteria provided, single submitter	clinical testing
GeneDx	RCV003105794	SCV003761787	uncertain significance	not provided	2023-01-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14704354)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003105794	SCV004220148	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	The RAD51C c.563A>T (p.Lys188Met) variant has been reported in the published literature in an individual affected with breast cancer (PMID: 31206626 (2019)). In addition, this variant was reported to display homology directed repair (HDR) activity similar to wildtype HDR activity (PMID: 37253112 (2023)). However, further studies are required to assess the global effect of this variant on RAD51C protein function. The frequency of this variant in the general population, 0.0002 (7/35438 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.