Submissions for variant NM_058216.3(RAD51C):c.745C>T (p.Arg249Cys)

dbSNP: rs28363311

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166138	SCV000216910	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	The p.R249C variant (also known as c.745C>T), located in coding exon 5 of the RAD51C gene, results from a C to T substitution at nucleotide position 745. The arginine at codon 249 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was detected once in a series of breast cancer only families but was absent from 314 breast/ovarian families, 21 ovarian cancer only families, and 427 healthy controls (Thompson ER et al. Hum Mutat. 2012 Jan; 33(1):95-9). In another study, this alteration was detected in a cohort of 1228 Danish breast and ovarian cancer families in an individual diagnosed with cervical cancer at age 35 whose mother was diagnosed with ovarian cancer at age 61 and maternal grandmother was diagnosed with breast cancer at ages 52 and 68. This individual also carried a pathogenic BRCA2 mutation (Jonson L et al. Breast Cancer Res Treat. 2016 Jan;155(2):215-22). 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.
Color Diagnostics, LLC DBA Color Health	RCV000166138	SCV000691265	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 249 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 4 suspected hereditary breast and ovarian cancer families including one in which a pathogenic BRCA2 covariant is also present (PMID: 21537932, 21990120, 23117857, 26740214). This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000013). This variant also has been reported in several cancer case-control studies in which the variant was found in unaffected control individuals but absent in breast, colorectal, pancreatic and biliary tract cancer cases (PMID: 32658311, 32980694, 35039523, 36243179). This variant has been identified in 1/251440 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	RCV000700952	SCV000829731	uncertain significance	Fanconi anemia complementation group O	2023-12-13	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 249 of the RAD51C protein (p.Arg249Cys). This variant is present in population databases (rs28363311, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21990120, 26740214). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in RAD51C in an individual who was not affected with recessive RAD51C-related conditions (Invitae). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 186529). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465553	SCV002760971	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465553	SCV004122901	uncertain significance	not specified	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.745C>T (p.Arg249Cys) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain (IPR013632) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-06 in 328440 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.745C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome as well as in healthy controls (Thompson_2011, Jnson_2016, Akcay_2020, Lim_2022, Okawa_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28829762, 26740214, 36243179, 21537932, 20052722, 21990120). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Leiden Open Variation Database	RCV001195024	SCV001365273	uncertain significance	not provided	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.