ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.26G>C (p.Cys9Ser) (rs140825795)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587404 SCV000149721 uncertain significance not provided 2021-08-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21111057, 31007844, 29522266, 25186627, 27498913, 28135145, 25340522, 24139550, 26261251, 22986143, 24130102, 21822267)
Ambry Genetics RCV000115812 SCV000185831 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-18 criteria provided, single submitter clinical testing The p.C9S variant (also known as c.26G>C), located in coding exon 1 of the RAD51D gene, results from a G to C substitution at nucleotide position 26. The cysteine at codon 9 is replaced by serine, an amino acid with dissimilar properties. This variant has been identified in numerous disease cohorts as well and unaffected control groups across studies (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Wickramanyake A et al. Gynecol. Oncol. 2012 Dec;127:552-5; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97). This amino acid position is highly 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.
Invitae RCV000231466 SCV000287702 likely benign Breast-ovarian cancer, familial 4 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000231466 SCV000488471 uncertain significance Breast-ovarian cancer, familial 4 2016-06-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115812 SCV000537513 likely benign Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587404 SCV000602155 uncertain significance not provided 2020-05-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175378 SCV000698094 likely benign not specified 2021-02-25 criteria provided, single submitter clinical testing Variant summary: RAD51D c.26G>C (p.Cys9Ser) results in a non-conservative amino acid change in 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 0.00037 in 258298 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2.97 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is benign. The variant, c.26G>C, has been reported in the literature in individuals affected with Breast and Ovarian Cancer or other cancers and also in controls (Wickramanyake_2012, Gutirrez-Enrquez_2013, Loveday_2011, Golmard_2013, Song_2015, Yurgelun_2017, Tung_2015, Madeddu_2019, Weitzel_2019). In addition, this variant has been reported in 10/9884 individuals who are at least 70 years old and cancer-free. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.5851_5854del, p.Ser1951Trpfs*11, Tung_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: two classified the variant as likely benign while eight classified the variant as a VUS. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587404 SCV000806577 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing
Mendelics RCV000709461 SCV000839205 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587404 SCV000861249 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000231466 SCV001434312 uncertain significance Breast-ovarian cancer, familial 4 2019-12-16 criteria provided, single submitter clinical testing This variant has been reported in the literature in individuals with breast and/or ovarian cancer (Wickramanayake 2012, Gutierrez-Enríquez 2014, Song 2015). This variant has an allele frequency of 0.0004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357793 SCV001553375 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The RAD51D p.Cys9Ser variant was identified in 9 of 12002 proband chromosomes (frequency: 0.0007) from Spanish, British and American individuals or families with BRCA1/2 negative breast/ovarian cancer or ovarian cancer and was identified in 3 of 7674 chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Loveday 2011, Wickramanayake 2012, Song 2015). A case-control study of 3,429 patients with invasive ovarian cancer (unselected for family history) and 2,772 controls sequenced for RAD51B/C/D mutations found that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes (Song 2015). The variant was identified in dbSNP (ID: rs140825795) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics Inc. and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and was not identified in Cosmic or LOVD 3.0. The variant was also identified in control databases in 109 (1 homozygous) of 273460 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 23938 chromosomes (freq: 0.0002), “Other” in 2 of 6436 chromosomes (freq: 0.0003), Latino in 13 (1 homozygous) of 34392 chromosomes (freq: 0.0004), European Non-Finnish in 88 of 124366 chromosomes (freq: 0.0007), European Finnish in 2 of 24602 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Cys9Ser 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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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