ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.353T>C (p.Ile118Thr) (rs200472836)

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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 RCV000130904 SCV000185813 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing The p.I118T variant (also known as c.353T>C), located in coding exon 3 of the RAD50 gene, results from a T to C substitution at nucleotide position 353. The isoleucine at codon 118 is replaced by threonine, an amino acid with similar properties. One study detected this alteration in 3/470 alleles from 235 Korean hereditary breast cancer patients (Kim H et al. Breast Cancer Res. Treat. 2017 01;161:95-102). 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.
Invitae RCV000130904 SCV000547999 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 118 of the RAD50 protein (p.Ile118Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs200472836, ExAC 0.2%). This variant has been reported in individual(s) with personal and/or family history of breast cancer (PMID: 27783279, 29338689). ClinVar contains an entry for this variant (Variation ID: 142082). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly 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.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030731 SCV001193699 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260375 SCV001437334 likely benign not specified 2020-09-14 criteria provided, single submitter clinical testing Variant summary: RAD50 c.353T>C (p.Ile118Thr) 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 6.8e-05 in 250462 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 14.9-fold 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 a benign polymorphism found primarily in populations of East Asian origin. c.353T>C has been reported in the literature in individuals affected with Hereditary Breast Cacner (e.g. Kim_2017). 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. 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. Based on the evidence outlined above, the variant was classified as likely benign.

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