ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.77A>T (p.Lys26Met) (rs746026526)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566177 SCV000667099 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000409148 SCV000489961 uncertain significance Fanconi anemia, complementation group O 2016-08-25 criteria provided, single submitter clinical testing
Counsyl RCV000410630 SCV000489962 uncertain significance Breast-ovarian cancer, familial 3 2016-08-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780669 SCV000918128 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: RAD51C c.77A>T (p.Lys26Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 282776 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.77A>T has been reported in the literature in individuals affected with Ovarian Cancer or glioma. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000409148 SCV000550192 uncertain significance Fanconi anemia, complementation group O 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with methionine at codon 26 of the RAD51C protein (p.Lys26Met). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is present in population databases (rs746026526, ExAC 0.003%). This variant has been reported in individuals affected with ovarian cancer and low grade glioma (PMID: 26261251, 26689913). ClinVar contains an entry for this variant (Variation ID: 372089). 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: "Probably Damaging"; 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.

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