Submissions for variant NM_058216.3(RAD51C):c.19C>G (p.Arg7Gly)

dbSNP: rs759759863

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701405	SCV000830205	uncertain significance	Fanconi anemia complementation group O	2023-04-26	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. ClinVar contains an entry for this variant (Variation ID: 578406). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is present in population databases (rs759759863, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 7 of the RAD51C protein (p.Arg7Gly).
Ambry Genetics	RCV002422570	SCV002721801	likely benign	Hereditary cancer-predisposing syndrome	2020-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689862	SCV005185483	uncertain significance	not specified	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.19C>G (p.Arg7Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251408 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.19C>G has been reported in the literature in at least one individuals affected with cancer (e.g., Bhai_2021). However, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function; studies evaluating the affect of the variant on RAD51C HR DNA repair activity showed no damaging effect. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 37253112). ClinVar contains an entry for this variant (Variation ID: 578406). Based on the evidence outlined above, the variant was classified as uncertain significance.