Submissions for variant NM_058216.3(RAD51C):c.1097G>A (p.Arg366Gln)

gnomAD frequency: 0.00001  dbSNP: rs577852020

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478660	SCV000568395	uncertain significance	not provided	2023-02-15	criteria provided, single submitter	clinical testing	Observed in at least one family with breast cancer and segregated with disease in two affected relatives; however, tumor analysis from one individual demonstrated no loss of heterozygosity (Meindl et al., 2010; Gevensleben et al., 2014); Published functional studies demonstrate reduced homologous recombination activity compared to wild-type, increased sensitivity to PARP inhibitors, and moderate sensitivity to DNA damaging agents, but no significant difference in RAD51 foci formation or interaction with RAD51B, RAD51D, XRCC2, or XRCC3 (Meindl et al., 2010; Somyajit et al., 2012; Somyajit et al., 2015; Mishra et al., 2018; Prakash et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25470109, 24993905, 25292178, 26740214, 20952512, 20400964, 14704354, 12966089, 36099300, 31567591, 29158291, 28829762, 34910513, 36562461, 22167183, 21537932)
Ambry Genetics	RCV000569753	SCV000671880	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-31	criteria provided, single submitter	clinical testing	The p.R366Q variant (also known as c.1097G>A), located in coding exon 9 of the RAD51C gene, results from a G to A substitution at nucleotide position 1097. The arginine at codon 366 is replaced by glutamine, an amino acid with highly similar properties. In a study of 1100 German high-risk breast and/or ovarian cancer families, this variant was detected in one family (Meindl A et al. Nat. Genet., 2010 May;42:410-4). Another study detected this variant in 1/492 breast cancer patients with family history of breast and/or ovarian cancer (Romero A et al. Breast Cancer Res. Treat., 2011 Oct;129:939-46). This variant was also identified in a cohort of individuals with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res, 2020 06;30:247-251). Functional studies have shown a reduction in homologous recombination activity from this alteration compared to wild-type protein (Somyajit K et al. Carcinogenesis, 2015 Jan;36:13-24). In another study, this alteration was shown to have reduced protein levels in the nucleus as compared to wild-type protein, but no change in protein levels in the mitochondria (Mishra A et al. Mol. Cell. Biol., 2018 02;38). However, in a homology-directed DNA repair (HDR) and PARP inhibitor and cisplatin sensitivity assay, this alteration showed a functionally normal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569753	SCV000691217	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 366 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting findings for this variant for which some have reported hypomorphic or partial loss-of-function (PMID: 20400964, 22167183, 25292178), while others reported no impact on normal binding to RAD51 paralogs, sensitivity to cisplatin and Olaparib treatment and function in a homology-directed repair assay (PMID: 36099300, 37253112). This variant has been reported in several individuals affected with personal or family history of breast or ovarian cancer (PMID: 20400964, 23117857, 25470109). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000025). This variant has been identified in 3/249618 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.
Invitae	RCV000648261	SCV000770075	uncertain significance	Fanconi anemia complementation group O	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 366 of the RAD51C protein (p.Arg366Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 20400964). ClinVar contains an entry for this variant (Variation ID: 420041). 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 affects RAD51C function (PMID: 20400964, 22167183). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mendelics	RCV001195031	SCV002519250	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153662	SCV003843766	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003464006	SCV004207992	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-06-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478660	SCV004220133	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/249618 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant is described to be hypomorphic resulting in partial loss of function (PMID: 25292178 (2015), 22167183 (2012)). Additionally, the variant was reported in an individual with familial breast and/or ovarian cancer (PMID: 20400964 (2010)). Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV001195031	SCV001365285	likely benign	not specified	2014-11-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.