Submissions for variant NM_058216.3(RAD51C):c.778C>T (p.Arg260Trp)

gnomAD frequency: 0.00002  dbSNP: rs374196453

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129567	SCV000184349	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-19	criteria provided, single submitter	clinical testing	The p.R260W variant (also known as c.778C>T), located in coding exon 5 of the RAD51C gene, results from a C to T substitution at nucleotide position 778. The arginine at codon 260 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197556	SCV000255194	uncertain significance	Fanconi anemia complementation group O	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 260 of the RAD51C protein (p.Arg260Trp). This variant is present in population databases (rs374196453, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and an individual undergoing genetic testing for hereditary cancer predisposition (PMID: 28135145, 31159747). ClinVar contains an entry for this variant (Variation ID: 141175). 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%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589224	SCV000602146	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000589224	SCV000616845	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer (PMID: 28135145); This variant is associated with the following publications: (PMID: 31159747, 14704354, 37253112, 28135145, 36099300)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589224	SCV000699824	uncertain significance	not provided	2017-07-28	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.778C>T (p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 2/121402 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant was found in one CRC patient in one study without strong evidence for causality (Yurgelun_CDH1_JCO_2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneKor MSA	RCV000129567	SCV000822173	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129567	SCV001358238	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 260 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 2/251438 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.
Baylor Genetics	RCV003467111	SCV004209768	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544291	SCV004781057	uncertain significance	RAD51C-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The RAD51C c.778C>T variant is predicted to result in the amino acid substitution p.Arg260Trp. This variant has been reported in an individual with colorectal cancer and an individual undergoing genetic testing for hereditary cancer predisposition syndromes (Table A4. Yurgelun et al 2017. PubMed ID: 28135145; Table S5. Tsaousis et al 2019. PubMed ID: 31159747). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141175/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.