Submissions for variant NM_058216.3(RAD51C):c.7G>A (p.Gly3Arg)

gnomAD frequency: 0.00003  dbSNP: rs376403182

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163662	SCV000214233	likely benign	Hereditary cancer-predisposing syndrome	2018-11-16	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.
Invitae	RCV000228544	SCV000291247	uncertain significance	Fanconi anemia complementation group O	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3 of the RAD51C protein (p.Gly3Arg). This variant is present in population databases (rs376403182, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer and head and neck squamous cell carcinoma (PMID: 20400964, 24315737, 25470109, 26261251, 26976419). ClinVar contains an entry for this variant (Variation ID: 184411). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 20400964). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
GeneDx	RCV000479892	SCV000567886	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: cell survival and RAD51 foci formation similar to wild-type (Meindl et al., 2010); Observed in individuals with breast, ovarian, and other cancers (Scheckenbach et al., 2014; Song et al., 2015; Tung et al., 2016); This variant is associated with the following publications: (PMID: 24315737, 26261251, 23117857, 26976419, 25470109, 21537932, 28829762, 33471991, 20400964)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163662	SCV000679742	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163662	SCV000902987	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 3 of the RAD51C protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant could restore normal mitomycin C sensitivity and RAD51 foci formation in the RAD51C mutant cells (PMID: 20400964). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 20400964, 25470109, 26261251, 26976419). This variant has been identified in 11/282672 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.
Sema4, Sema4	RCV000163662	SCV002530019	likely benign	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	curation
Leiden Open Variation Database	RCV001195006	SCV001365238	likely benign	not specified	2014-11-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.