Submissions for variant NM_058216.3(RAD51C):c.506T>C (p.Val169Ala)

gnomAD frequency: 0.00009  dbSNP: rs587780256

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588889	SCV000150084	likely benign	not provided	2021-02-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26689913, 18203022, 28829762, 21537932, 20400964, 25470109, 22370629, 22476429, 25980754, 21990120, 25801821, 27443514, 23117857, 26261251, 22538716)
Ambry Genetics	RCV000116175	SCV000186092	likely benign	Hereditary cancer-predisposing syndrome	2018-11-08	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	RCV000199007	SCV000255189	uncertain significance	Fanconi anemia complementation group O	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 169 of the RAD51C protein (p.Val169Ala). This variant is present in population databases (rs587780256, gnomAD 0.03%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 18203022, 20400964, 21990120, 22370629, 22476429, 22538716, 25980754, 26689913, 27443514, 34326862). This variant is also known as 4150T>C. ClinVar contains an entry for this variant (Variation ID: 128206). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 20400964). 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.
Counsyl	RCV000199007	SCV000489891	uncertain significance	Fanconi anemia complementation group O	2016-07-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000412269	SCV000489892	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-07-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116175	SCV000691242	likely benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588889	SCV000699815	benign	not provided	2016-03-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000412269	SCV001428697	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2021-07-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116175	SCV002531824	likely benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267859	SCV002551132	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412269	SCV004017737	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-06	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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588889	SCV004220144	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22538716 (2012), 21990120 (2012), 22370629 (2012), 22476429 (2012), and 20400964 (2010)). The variant has also been identified in individuals affected with either a history of Lynch syndrome-associated cancer and/or polyps, B-cell chronic lymphocytic leukemia, endometrial carcinoma, or low grade glioma (PMID: 27443514 (2016), 26689913 (2015), 25980754 (2015), 18203022 (2008)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). Assessment of experimental studies yielded non-damaging results regarding the impact of this variant on protein function (PMID: 20400964 (2010)). The frequency of this variant in the general population, 0.00033 (42/129164 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492509	SCV004239988	uncertain significance	Breast and/or ovarian cancer	2022-11-14	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV004556053	SCV005045402	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358061	SCV001553705	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Val169Ala variant was identified in 11 of 30,036 proband chromosomes (frequency: 0.0004) from individuals or families with chronic lymphocytic leukemia, Lynch Syndrome, glioma, endometrial, and hereditary breast and ovarian cancer and was present in 2 of 16,372 control chromosomes (frequency: 0.0001) from healthy individuals (Sellick 2008, Meindl 2009, Lu 2012, De Leeneer 2012, Thompson 2012, Loveday 2012, Yurgelun 2015, Ring 2016, Lu 2015, Song 2015). The variant was identified in dbSNP (rs587780256) as “with uncertain significance allele”, in ClinVar (classified as likely benign by Ambry Genetics, Color and GeneDx, uncertain significance by Invitae and Counsyl and benign by Integrated Genetics) and LOVD 3.0 (observed 4x). The variant was identified in control databases in 42 of 282,840 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 42 of 129,164 chromosomes (freq: 0.0003); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. In one study in vitro expressio n of the variant had a similar effect on cell survival and RAD51C protein expression compared to wild type (Meindl 2009). The p.Val169 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000588889	SCV001906096	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588889	SCV001959124	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588889	SCV001972020	likely benign	not provided		no assertion criteria provided	clinical testing