ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.715C>T (p.Arg239Trp) (rs770250516)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166936 SCV000217755 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-25 criteria provided, single submitter clinical testing The p.R239W variant (also known as c.715C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 715. The arginine at codon 239 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is reported to co-occur with the p.R232* (c.694C>T) pathogenic RAD51D mutation in a proband with ovarian cancer at age 43 (Wickramanyake A et al. Gynecol. Oncol. 2012 Dec;127:552-5). In another family, both alterations were found in a proband with ovarian cancer at age 44 and in four of her healthy siblings (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97). Both of these alteration are also reported in a third family with two sisters with ovarian cancer at ages 47 and 46 and their three unaffected children (Sanchez-Bermudez AI et al. Eur J Med Genet. 2018 Jun;61(6):355-361). This variant was reported in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000236062 SCV000292681 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.715C>T at the cDNA level, p.Arg239Trp (R239W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). RAD51D Arg239Trp has been observed in at least five women with ovarian cancer, four of whom are reported to also carry the pathogenic variant RAD51D Arg232Ter (Wickramanayake 2012, Gutierrez-Enr?quez 2014, Song 2015, Sanchez-Bermudez 2018). RAD51D Arg239Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in RAD51C binding domain (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 Arg239Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409739 SCV000488994 uncertain significance Breast-ovarian cancer, familial 4 2016-08-02 criteria provided, single submitter clinical testing
Invitae RCV000409739 SCV000551328 uncertain significance Breast-ovarian cancer, familial 4 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 239 of the RAD51D protein (p.Arg239Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs770250516, ExAC 0.004%). This variant has been observed in individuals and families affected with ovarian cancer (PMID: 22986143, 26261251, 24130102, 29409816). In both affected individuals and unaffected siblings, a pathogenic RAD51D variant c.694C>T (p.Arg232*) was also identified (PMID: 22986143, 24130102, 29409816). ClinVar contains an entry for this variant (Variation ID: 187225). 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: Benign; Align-GVGD: Class C0). 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.
Mendelics RCV000709437 SCV000839179 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236062 SCV000888609 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000409739 SCV000895089 uncertain significance Breast-ovarian cancer, familial 4 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166936 SCV000902844 likely benign Hereditary cancer-predisposing syndrome 2015-11-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236062 SCV001151268 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236062 SCV001553159 uncertain significance not provided no assertion criteria provided clinical testing The RAD51D p.Arg239Trp variant was identified in 8 of 10584 proband chromosomes (frequency: 0.0008) from individuals or families with breast or ovarian cancer and was not identified in 5624 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Sanchez-Bermudez 2018, Song 2015, Wickramanayake 2012). The variant was also identified in several population studies with a co-occurring pathogenic RAD51D variant (c.694C>T, p.Arg232*) in multiple members of same families (Sanchez-Bermudez 2018, Gutierrez-Enriquez 2013, Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs770250516) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and four other submitters). The variant was identified in control databases in 9 of 271100 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6340 chromosomes (freq: 0.0002), European in 5 of 123902 chromosomes (freq: 0.00004), East Asian in 2 of 18598 chromosomes (freq: 0.0001), and South Asian in 1 of 29868 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Arg239 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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