Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001797586 | SCV002041789 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2021-11-03 | criteria provided, single submitter | clinical testing | Variant summary: RAD51C c.374G>T (p.Gly125Val) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain (IPR020588) and Rad51/DMC1/RadA domain (IPR033925) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250090 control chromosomes (gnomAD). c.374G>T has been reported in the literature in 3 females from the same family affected with Hereditary Breast And Ovarian Cancer (Meindl_2010). Experimental evidence demonstrated that expression of the variant in cells, exhibited survival identical to control vector RAD51C-deficient cells, and failed to restore normal RAD51 foci formation (Meindl_2010). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Labcorp Genetics |
RCV003507247 | SCV004297489 | likely pathogenic | Fanconi anemia complementation group O | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 125 of the RAD51C protein (p.Gly125Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or hereditary breast and ovarian cancer (PMID: 20400964). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6824). 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 expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 22167183, 23438602, 25292178, 36562461). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
OMIM | RCV000007226 | SCV000027422 | risk factor | Breast-ovarian cancer, familial, susceptibility to, 3 | 2010-05-01 | no assertion criteria provided | literature only | |
Leiden Open Variation Database | RCV001195016 | SCV001365255 | pathogenic | not provided | 2020-02-28 | no assertion criteria provided | curation | Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. |