ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1277A>G (p.Gln426Arg) (rs145428112)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212909 SCV000149838 uncertain significance not provided 2014-02-17 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.1277A>G at the cDNA level, p.Gln426Arg (Q426R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Gln426Arg has not been observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a a neutral polar amino acid is replaced with a positive polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics RCV000115929 SCV000186121 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing The p.Q426R variant (also known as c.1277A>G), located in coding exon 9 of the RAD50 gene, results from an A to G substitution at nucleotide position 1277. The glutamine at codon 426 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in multiple studies of individuals with suspected hereditary breast and/or ovarian cancer syndrome, including patients with male breast cancer, ovarian cancer, and bilateral breast cancer (Urhammer N and Bignon YJ. "Abstract# 3037: Contribution of the Rad50, Mre11A, and NBN genes to HBOC." Cancer Res.2009;69; Koczkowska M et al. Cancers (Basel), 2018 Nov;10;442; Oliver J et al. Front Oncol., 2019 Dec;9:1429; Scarpitta R et al. Breast Cancer Res. Treat., 2019 Dec;178:557-564; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Fanale D et al. Cancers (Basel), 2020 Aug;12:E2415). However, in another study, this variant was not observed in 1313 cases diagnosed with breast cancer before the age of 45 but was reported in 1/1123 controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This amino acid position is highly 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 RCV000115929 SCV000254876 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 426 of the RAD50 protein (p.Gln426Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs145428112, ExAC 0.03%). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 31512090, 31921681, 30441849, Invitae). ClinVar contains an entry for this variant (Variation ID: 127993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Fulgent Genetics,Fulgent Genetics RCV000515382 SCV000611509 uncertain significance Nijmegen breakage syndrome-like disorder 2017-05-23 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115929 SCV000822143 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175422 SCV001338970 likely benign not specified 2020-03-17 criteria provided, single submitter clinical testing Variant summary: RAD50 c.1277A>G (p.Gln426Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 244864 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00026 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1277A>G, has been reported in the literature in individuals with a personal- or family history of Breast and/or Ovarian Cancer, and other tumor phenotypes (Koczkowska_2018, Scarpitta_2019, Oliver_2019, Tsaousis_2019), however it was also found in controls (Haiman_2013, Damiola_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In addition, in a patient who was affected with thyroid cancer, a co-occurrence with another pathogenic variant has been reported (CHEK2 c.444+1G>A; Henn_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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