ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.137C>G (p.Ser46Cys) (rs587780102)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656964 SCV000149717 uncertain significance not provided 2021-01-20 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22986143, 27616075, 21822267)
Ambry Genetics RCV000115808 SCV000185614 likely benign Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study
Invitae RCV000228533 SCV000287698 uncertain significance Breast-ovarian cancer, familial 4 2020-10-22 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 46 of the RAD51D protein (p.Ser46Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs587780102, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with ovarian and breast cancer (PMID: 22986143, 27616075), and an individual affected with multiple adenomatous polyps (PMID: 25938944). ClinVar contains an entry for this variant (Variation ID: 127882). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212953 SCV000604997 uncertain significance not specified 2016-11-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115808 SCV000686419 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 46 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer and/or ovarian cancer (PMID: 21822267, 22986143, 27616075) and colorectal polyposis (PMID: 25938944) and in individuals age 70 years or older without cancer (FLOSSIES; https://whi.color.com/variant/17-33446137-G-C). This variant has also been identified in 22/282706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000228533 SCV000784997 uncertain significance Breast-ovarian cancer, familial 4 2017-03-15 criteria provided, single submitter clinical testing
Mendelics RCV000709453 SCV000839197 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354278 SCV001548855 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The RAD51D p.Ser46Cys variant was identified in 1 of 1172 proband chromosomes (frequency: 0.0009) from individuals or families with unselected ovarian cancer or at high risk of breast cancer (and negative for breast and ovarian cancer genes); it was identified in an ovarian cancer case (Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs587780102) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics, Invitae, ARUP Laboratories and Color Genomics Inc), and Clinvitae (3x), but was not identified in Cosmic and LOVD 3.0. The variant was identified in control databases in 25 of 276898 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 4 of 34418 chromosomes (freq: 0.0001) and European Non-Finnish in 20 of 126540 chromosomes (freq: 0.0002); but not in the African, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ser46 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 Cys 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, 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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