Submissions for variant NM_058216.3(RAD51C):c.772C>T (p.Arg258Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782474

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131582	SCV000186592	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	The p.R258C variant (also known as c.772C>T), located in coding exon 5 of the RAD51C gene, results from a C to T substitution at nucleotide position 772. The arginine at codon 258 is replaced by cysteine, an amino acid with highly dissimilar properties. Another alteration at the same codon, p.R258H, has been described as a homozygous alteration causative of Fanconi anemia type O (FA-O) in a consanguineous Pakistani kindred (Vaz F et al. Nat Genet. 2010 May;42(5):406-9). The p.R258C variant was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Invitae	RCV000460132	SCV000550232	uncertain significance	Fanconi anemia complementation group O	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the RAD51C protein (p.Arg258Cys). This variant is present in population databases (rs587782474, gnomAD 0.006%). This missense change has been observed in individual(s) with lung squamous cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142453). 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%. This variant disrupts the p.Arg258 amino acid residue in RAD51C. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20400963, 25154786, 26740214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000679803	SCV000565460	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26689913, 27149507, 14704354, 25292178)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484433	SCV000602144	uncertain significance	not specified	2016-12-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131582	SCV000686386	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 258 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. However, a different variant (p.Arg258His) affecting the same codon is considered to be disease-causing (ClinVar variation ID: 6822), suggesting that arginine at this position is important for the protein function. This variant has been reported in an individual affected with lung squamous cell carcinoma (PMID: 26689913). This variant has been identified in 7/251434 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.
Counsyl	RCV000662865	SCV000785750	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-11-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679803	SCV000807178	uncertain significance	not provided	2016-05-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000662865	SCV002791649	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-04-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315911	SCV004019931	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003315911	SCV004207938	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-09-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355151	SCV001549945	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Arg258Cys variant was identified in 1 of 2456 proband chromosomes (frequency: 0.0004) from Danish individuals or families with breast or ovarian cancer (Jonson 2015). The variant was identified in a Pakistani woman with a family history of breast cancer, co-occurring with a BRCA2 variant (c.9648G>A, p.Leu3216Leu), which was found to cause exon 26 skipping by a minigene splicing assay (Ahlborn 2015). A different missense variant at the same residue (p.Arg258His) was identified in the homozygous state in a consanguineous Pakistani family with multiple severe congenital abnormalities characteristic of Fanconi anemia (Vaz 2010). The variant was identified in dbSNP (ID: rs587782474) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color, Counsyl, Prevention Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 7 of 246218 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 7 of 111674 chromosomes (freq: 0.00006); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Arg258 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.