ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.200A>G (p.Glu67Gly)

gnomAD frequency: 0.00012  dbSNP: rs375451955
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212936 SCV000211624 uncertain significance not provided 2023-09-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (PMID: 28864920); This variant is associated with the following publications: (PMID: 28864920)
Ambry Genetics RCV000160920 SCV000215378 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-22 criteria provided, single submitter clinical testing The p.E67G variant (also known as c.200A>G), located in coding exon 2 of the RAD51C gene, results from an A to G substitution at nucleotide position 200. The glutamic acid at codon 67 is replaced by glycine, an amino acid with similar properties. This alteration was detected in a cohort of African American females diagnosed with breast cancer under age 50 and/or a family history of breast and/or ovarian cancers (Ding YC et al. Fam Cancer. 2018 04;17:187-195). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000227460 SCV000291215 uncertain significance Fanconi anemia complementation group O 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 67 of the RAD51C protein (p.Glu67Gly). This variant is present in population databases (rs375451955, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 182832). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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 Diagnostics, LLC DBA Color Health RCV000160920 SCV000686332 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-24 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glycine at codon 67 of the RAD51C 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 11/282858 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731409 SCV001983682 uncertain significance not specified 2023-03-03 criteria provided, single submitter clinical testing Variant summary: RAD51C c.200A>G (p.Glu67Gly) 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 3.2e-05 in 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.200A>G has been reported in the literature in an individual affected with breast cancer (Ding_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago RCV001731409 SCV002070443 uncertain significance not specified 2021-11-29 criteria provided, single submitter clinical testing DNA sequence analysis of the RAD51C gene demonstrated a sequence change, c.200A>G, in exon 2 that results in an amino acid change, p.Glu67Gly. This sequence change has been described in the gnomAD database with a frequency of 0.04% in the African/African American subpopulation (dbSNP rs375451955). The p.Glu67Gly change affects a moderately conserved amino acid residue located in a domain of the RAD51C protein that is known to be functional. The p.Glu67Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with RAD51C-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu67Gly change remains unknown at this time.
Sema4, Sema4 RCV000160920 SCV002531803 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-24 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002478491 SCV002784412 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O 2022-05-22 criteria provided, single submitter clinical testing

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