ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1663A>G (p.Ile555Val) (rs201120953)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000030960 SCV000053550 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-28 criteria provided, single submitter clinical testing The p.I555V variant (also known as c.1663A>G), located in coding exon 11 of the RAD50 gene, results from an A to G substitution at nucleotide position 1663. The isoleucine at codon 555 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 2/96 patients with pancreatic ductal adenocarcinoma, unselected for family history, who underwent a 22 gene panel test (Hu C et al. Cancer Epidemiol. Biomarkers Prev. 2016 Jan;25:207-11). This amino acid position is 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 RCV000030960 SCV000261755 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 555 of the RAD50 protein (p.Ile555Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201120953, ExAC 0.01%). This variant has been reported in two individuals affected with pancreatic cancer (PMID: 26483394). ClinVar contains an entry for this variant (Variation ID: 37379). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneKor MSA RCV000030960 SCV000822146 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 RCV001375596 SCV001572498 likely benign not specified 2021-04-04 criteria provided, single submitter clinical testing Variant summary: RAD50 c.1663A>G (p.Ile555Val) 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 allele was found at a frequency of 8e-05 in 250738 control chromosomes. The observed variant frequency is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. c.1663A>G has been reported in the literature in settings of multigene panel testing performed on at-least one individual from a pancreatic cancer registry who was unselected for a family history of cancer (example, Hu_2016) and in settings of multigene panel testing on individuals with breast/ovarian cancer (example, Gpoidescu_2018, Tsaousis_2019, Sandoval_2021, Akcay_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome/RAD50 related cancer. 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. All laboratories classified the variant as uncertain significance. Some submitters cite at-least one overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

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