ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.413A>G (p.Asn138Ser) (rs201676898)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212959 SCV000149724 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.413A>G at the cDNA level, p.Asn138Ser (N138S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as RAD51D 473A>G or Asn158Ser. This variant has been observed in individuals with breast, endometrial, ovarian, pancreatic, and prostate cancer, as well as in at least one healthy control (Johnson 2014, Tung 2015, Ring 2016, Shindo 2017, Sanchez-Bermudez 2018). RAD51D Asn138Ser was observed at an allele frequency of 0.055% (19/34418 alleles) in individuals of Latino ancestry in large population cohorts (Lek 2016). RAD51D Asn138Ser is located in the RAD51C binding domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51D Asn138Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115815 SCV000185137 likely benign Hereditary cancer-predisposing syndrome 2019-02-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Other strong data supporting benign classification;In silico models in agreement (benign)
Invitae RCV000232930 SCV000287711 uncertain significance Breast-ovarian cancer, familial 4 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 138 of the RAD51D protein (p.Asn138Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs201676898, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with prostate cancer, endometrial cancer, breast cancer, ovarian cancer, and pancreatic ductal adenocarcinoma (PMID: 25111073, 25186627, 27443514, 28767289, 29409816). This variant is also known as c.473T>C (p.N158S) in the literature. ClinVar contains an entry for this variant (Variation ID: 127889). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Counsyl RCV000232930 SCV000488855 uncertain significance Breast-ovarian cancer, familial 4 2016-07-05 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115815 SCV000822179 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000115815 SCV000910644 likely benign Hereditary cancer-predisposing syndrome 2014-12-23 criteria provided, single submitter clinical testing

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