Submissions for variant NM_005732.4(RAD50):c.670C>T (p.Arg224Cys)

dbSNP: rs753136372

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214654	SCV000274892	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	The p.R224C variant (also known as c.670C>T), located in coding exon 5 of the RAD50 gene, results from a C to T substitution at nucleotide position 670. The arginine at codon 224 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has previously been reported in an Irish female diagnosed with breast cancer (Aloraifi F et al. FEBS J. 2015 Sep;282:3424-37). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000214654	SCV000548030	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	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 224 of the RAD50 protein (p.Arg224Cys). This variant is present in population databases (rs753136372, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 231137). 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 RAD50 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	RCV002478791	SCV002774718	uncertain significance	not provided	2021-07-06	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003327385	SCV004034296	uncertain significance	Familial cancer of breast	2023-09-13	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 224 of the RAD50 protein (p.Arg224Cys). This variant is present in population databases (rs753136372, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 231137). This amino acid position is not well conserved (PhyloP=1.79) . In addition, this alteration is predicted to be tolerated by in silico analysis. 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.
PreventionGenetics, part of Exact Sciences	RCV003401140	SCV004105404	uncertain significance	RAD50-related condition	2023-01-23	criteria provided, single submitter	clinical testing	The RAD50 c.670C>T variant is predicted to result in the amino acid substitution p.Arg224Cys. This variant was reported in an individual with Breast cancer (Table S1, Aloraifi et al 2015. PubMed ID: 26094658). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131915672-C-T). A different variant affecting the same amino acid (p.Arg224His) was reported in individuals with breast /ovarian cancer (Figure 1, Tommiska. 2006. PubMed ID: 16385572; Heikkinen. 2003. PubMed ID: 14684699). In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/231137/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003462455	SCV004207356	uncertain significance	Nijmegen breakage syndrome-like disorder	2023-08-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479067	SCV004222962	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.670C>T (p.Arg224Cys) results in a non-conservative amino acid change located in the Rad50/SbcC-type AAA domain (IPR038729) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251138 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.670C>T has been reported in the literature in at-least one individual affected with non-BRCA1/2 familial breast cancer (Aloraifi_2015). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, but was also found in 2/53461 controls (Dorling_2021 through LOVD). These report(s) 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: 26094658, 33471991). 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.