ClinVar Miner

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

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Total submissions: 7
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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 2020-10-07 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 2021-03-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, and colon cancer (Lu 2015, Pearlman 2017, Momozawa 2018); This variant is associated with the following publications: (PMID: 26689913, 30287823, 27978560)
Counsyl RCV000229485 SCV000797968 uncertain significance Ataxia-telangiectasia syndrome 2018-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165761 SCV000903358 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing [draft report note] This missense variant replaces isoleucine with valine at codon 238 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26689913) and colorectal cancer (PMID: 27978560). This variant has been identified in 4/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196993 SCV001367628 uncertain significance Familial cancer of breast 2020-03-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287228 SCV001473895 uncertain significance none provided 2020-02-01 criteria provided, single submitter clinical testing The ATM c.712A>G; p.Ile238Val variant (rs754275014) is reported in the literature in an individual with colorectal cancer (Pearlman 2017), and individuals with breast cancer but was also reported in healthy controls (Momozawa 2018). This variant is reported in the ClinVar database (Variation ID: 186210). It is found in the general population with an overall allele frequency of 0.002% (4/251040 alleles) in the Genome Aggregation Database. The isoleucine at codon 238 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471.

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