ClinVar Miner

Submissions for variant NM_001142571.2(RAD51D):c.553C>T (p.Arg185Trp) (rs544654228)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212962 SCV000149726 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.493C>T at the cDNA level, p.Arg165Trp (R165W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). In a case-control study, this variant was not observed in individuals with ovarian cancer, but was observed in one healthy control (Song 2015). This variant was also observed to co-occur with a pathogenic ATM variant in a woman with breast cancer (Dominguez-Valentin 2018). RAD51D Arg165Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51C binding region (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51D Arg165Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115817 SCV000214921 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000234729 SCV000287714 uncertain significance Breast-ovarian cancer, familial 4 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 165 of the RAD51D protein (p.Arg165Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs544654228, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 127891). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Color RCV000115817 SCV000686463 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115817 SCV000822181 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212962 SCV000889825 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781805 SCV000920136 uncertain significance not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: RAD51D c.493C>T (p.Arg165Trp) results in a non-conservative amino acid change located in the following domains of the encoded protein sequence: DNA recombination and repair protein Rad51-like, C-terminal domain; DNA recombination and repair protein RecA-like, ATP-binding domain; AAA+ ATPase domain. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 285080 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer (4.9e-05 vs 0.00013), allowing no conclusion about variant significance. c.493C>T has been reported in the literature in one individual affected with Breast Cancer that was also a carrier of another variant (ATM c.9139C>T/p.Arg3047Ter, classified Pathogenic/Likely pathogenic in ClinVar). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Cancer Genetics and Family Consultants,Athens Medical Center RCV000786005 SCV000924305 likely pathogenic Lynch syndrome I 2019-06-05 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.493C>T at the DNA level, p.Arg165Trp. The arginine residue is weakly conserved and there is a moderate physicochemical difference between Arginine and Tryptophan. This variant has not been reported in the literature in individuals with RAD51D related disease. It has never been reported so far in Greek population. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We observed this variant in a woman with ovarian cancer at the age of 44 years and her brother with undifferentiated gastric cancer at the age of 43 years. Two other sisters are healthy carriers at the age of 53 and 50 years. There was also ovarian and prostate cancer in second degree family members, from the paternal side. The phenotype in this family was consistent with Lynch Syndrome type II. This inherited syndrome in the above family has apparently a causative relation with RAD51D mutation c.493C>T, which is classified as likely pathogenic.
True Health Diagnostics RCV000115817 SCV000788206 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-05 no assertion criteria provided clinical testing

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