ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.355T>C (p.Cys119Arg) (rs201313861)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586341 SCV000211652 uncertain significance not provided 2021-07-19 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, pancreatic, and other cancers (Osher 2012, Song 2015, Penkert 2018, Shindo 2017); This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148, 27535533, 30086788, 28492532, 26261251, 24130102, 22415235, 28767289)
Ambry Genetics RCV000160945 SCV000214018 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-10 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 detected in Belgian and Spanish individuals from an ovarian and/or breast cancer family that have previously tested negative for mutations in BRCA1/2 (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). 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 4 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 119 of the RAD51D protein (p.Cys119Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs201313861, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22415235, 24130102, 26261251), and in individuals affected with pancreatic ductal adenocarcinoma (PMID: 28767289). This variant is also known as c.415A>G (p.C139R) in the literature. ClinVar contains an entry for this variant (Variation ID: 182856). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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 and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc 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
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.

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