ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.712A>G (p.Ile238Val) (rs754275014)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165761 SCV000216506 likely benign Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000229485 SCV000283039 uncertain significance Ataxia-telangiectasia syndrome 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 238 of the ATM protein (p.Ile238Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs754275014, ExAC 0.003%). This variant has been reported in individuals affected with colorectal cancer, breast cancer, and ovarian cancer (PMID: 27978560, 30287823, 26689913). ClinVar contains an entry for this variant (Variation ID: 186210). 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.
GeneDx RCV000235409 SCV000293178 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.712A>G at the cDNA level, p.Ile238Val (I238V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been reported in an individual with colon cancer and another with ovarian cancer (Lu 2015, Pearlman 2017). ATM Ile238Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Ile238Val is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ile238Val is pathogenic or benign. We consider it to be a variant of unknown significance.
Counsyl RCV000229485 SCV000797968 uncertain significance Ataxia-telangiectasia syndrome 2018-02-23 criteria provided, single submitter clinical testing
Color RCV000165761 SCV000903358 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-16 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196993 SCV001367628 uncertain significance Breast carcinoma; Intestinal polyp 2020-03-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.

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