Submissions for variant NM_002878.4(RAD51D):c.355T>C (p.Cys119Arg)

gnomAD frequency: 0.00008  dbSNP: rs201313861

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586341	SCV000211652	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, pancreatic, and other cancers (Osher et al., 2012; Song et al., 2015; Shindo et al., 2017; Penkert et al., 2018); This variant is associated with the following publications: (PMID: 28767289, 22415235, 24130102, 26261251, 28492532, 30086788, 14704354, 19327148, 21111057, 34923718, 27535533)
Ambry Genetics	RCV000160945	SCV000214018	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.C119R variant (also known as c.355T>C), located in coding exon 5 of the RAD51D gene, results from a T to C substitution at nucleotide position 355. The cysteine at codon 119 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts (Osher DJ et al. Br. J. Cancer, 2012 Apr;106:1460-3; Gutiérrez-Enríquez S et al. Int J Cancer, 2014 May;134:2088-97; Tung N et al. Cancer, 2015 Jan;121:25-33; Song H et al. J Clin Oncol, 2015 Sep;33:2901-7; Penkert J et al. Breast Cancer Res, 2018 08;20:87). Additionally, this variant was reported in 8/60,466 breast cancer cases and in 9/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Invitae	RCV000227224	SCV000287709	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 119 of the RAD51D protein (p.Cys119Arg). This variant is present in population databases (rs201313861, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic ductal adenocarcinoma (PMID: 22415235, 24130102, 25186627, 26261251, 28767289, 30086788). This variant is also known as c.415A>G (p.C139R). ClinVar contains an entry for this variant (Variation ID: 182856). 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 RAD51D protein function with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420703	SCV000698099	uncertain significance	not specified	2021-04-16	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.355T>C (p.Cys119Arg) results in a non-conservative amino acid change located in the AAA+ ATPase domain of 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 5.8e-05 in 256850 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (5.8e-05 vs 0.00013), allowing no conclusion about variant significance. c.355T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome in the absence of BRCA mutations, as well as pancreatic cancer and prostate cancer (Osher_2012, Gutierrez-Enriques_2014, Song_2015, Tung_2015, Shindo_2017, Lu_2015, Penkert_2018). These reports do 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; five classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000709444	SCV000839188	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160945	SCV000910862	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586341	SCV001470089	uncertain significance	not provided	2019-10-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798559	SCV002043217	uncertain significance	Breast and/or ovarian cancer	2021-04-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160945	SCV002534805	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001420703	SCV002550924	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000227224	SCV004208081	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-10-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354078	SCV001548605	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Cys119Arg variant was identified in 4 of 8892 proband chromosomes (frequency: 0.0004) from individuals or families with breast and ovarian cancer and was present in 2 of 5544 control chromosomes (frequency: 0.0004) from healthy individuals (Gutierrez-Enriquez 2013, Osher 2012, Song 2015). The variant was also identified in dbSNP (ID: rs201313861) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by GeneDx, Ambry genetics, Invitae, LCOA clinical laboratory). The variant was not identified in the Cosmic database. The variant was identified in control databases in 15 of 277134 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Latino in 3 of 34420 chromosomes (freq: 0.0001), European in 11 of 126692 chromosomes (freq: 0.0001); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys119 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.