Submissions for variant NM_058216.3(RAD51C):c.859A>G (p.Thr287Ala)

gnomAD frequency: 0.00653  dbSNP: rs28363317

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119137	SCV000153852	benign	Fanconi anemia complementation group O	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212950	SCV000171268	benign	not specified	2013-10-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000130980	SCV000185897	benign	Hereditary cancer-predisposing syndrome	2014-06-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000212950	SCV000297363	benign	not specified	2015-07-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000305956	SCV000404323	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000341847	SCV000404324	likely benign	Breast and Ovarian Cancer Susceptibility	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000119137	SCV000489833	likely benign	Fanconi anemia complementation group O	2016-06-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000411553	SCV000489834	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2016-06-13	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000426921	SCV000511148	likely benign	not provided	2016-10-10	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000130980	SCV000537377	benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212950	SCV000596686	benign	not specified	2017-06-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000426921	SCV000692917	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	RAD51C: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426921	SCV000699827	benign	not provided	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.859A>G (p.Thr287Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 693/126274 control chromosomes (3 homozygotes) at a frequency of 0.0054881, which is approximately 88 times the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients (including BrC, OvC, PcC) and some studies reported comparable frequencies of variant in case and controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign, without evidence to independently evaluate. Complementation assays of T287A have shown that a normal number of RAD51C foci are formed. Cells survival is reduced by ~36% in chicken DT40 cells, which may not be replicated in mammalian cells or associated with the pathology of HBOC (Meindl_2010). Considering all evidence, this variant is classified as benign.
Eurofins Ntd Llc (ga)	RCV000212950	SCV000854935	benign	not specified	2018-08-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000426921	SCV000888606	benign	not provided	2022-06-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000119137	SCV001140725	benign	Fanconi anemia complementation group O	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000426921	SCV001474615	benign	not provided	2023-10-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798371	SCV002043695	benign	Breast and/or ovarian cancer	2022-02-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130980	SCV002530023	benign	Hereditary cancer-predisposing syndrome	2021-05-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212950	SCV002551142	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411553	SCV004017713	benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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].
Breakthrough Genomics, Breakthrough Genomics	RCV000426921	SCV005211129	likely benign	not provided		criteria provided, single submitter	not provided
True Health Diagnostics	RCV000130980	SCV000788202	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528822	SCV000807181	benign	RAD51C-related disorder	2019-03-01	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354676	SCV001549352	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Thr287Ala variant was identified in 57 of 8266 proband chromosomes (frequency: 0.007) from Australian, British, German, American, Jewish and Other individuals or families with non- BRCA1/BRCA2 (high risk or familial) breast and/or ovarian cancer and was identified in 35 of 6604 control chromosomes (frequency: 0.005) from healthy individuals (Thompson 2012, Neidhardt 2017, Meindl 2009, Lu 2012, Clague 2011, Kushnir 2012, Leeneer 2012, Lu 2012). Three groups assessed RAD51C protein function for this variant, genomic stability and homologous recombination through functional assays and found that the variant is hypomorphic (Meindl 2009, Somyajit 2012, Clague 2011). However, complementation studies of this variant with a mutant RAD51C human fibroblast cell line demonstrated correction of the phenotype. The variant was also identified in dbSNP (ID: rs28363317) as “Other”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics, Children's Hospital of Philadelphia, Color Genomics; and likely benign by Illumina, Counsyl, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics), and LOVD 3.0 (9X); but was not identified in Clinvitae, Cosmic, and MutDB databases. The variant was identified in control databases in 1542 (6 homozygous) of 276966 chromosomes at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The p.Thr287Ala residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212950	SCV001809406	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000426921	SCV001906011	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212950	SCV001953716	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000426921	SCV001974217	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001729395	SCV001977042	likely benign	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000426921	SCV001979826	likely benign	not provided		no assertion criteria provided	clinical testing