ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2209C>G (p.Gln737Glu) (rs549559726)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167368 SCV000218220 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000167368 SCV000628195 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 737 of the RAD50 protein (p.Gln737Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs549559726, ExAC 0.2%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 187622). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000764585 SCV000895676 uncertain significance Nijmegen breakage syndrome-like disorder 2018-10-31 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030506 SCV001193706 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001194195 SCV001363540 likely benign not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: RAD50 c.2209C>G (p.Gln737Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant is located close to a canonical splice site therefore could affect splicing: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.3e-05 in 247246 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequencies within East Asian control individuals in the gnomAD database is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. In addition, in certain East Asian subpopulations the variant was reported with even higher frequencies, e.g. in the Koreans (0.0032; in gnomAD) and in the Japanese (0.0040; in the jMorp database), further supporting a benign role of the variant. The variant c.2209C>G has been reported in the literature in two Japanese individuals affected with biliary tract carcinoma (Terashima_2019), however without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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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