ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3963G>A (p.Met1321Ile) (rs35184530)

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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 RCV000129195 SCV000183934 likely benign Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: No disease association in small case-control study,In silico models in agreement (benign)
Color RCV000129195 SCV000910722 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000657024 SCV000566628 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.3963G>A at the cDNA level, p.Met1321Ile (M1321I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed in one control individual (1/2245) and was absent from breast cancer cases (0/2531) in a large meta-analysis and was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Tavtigian 2009, Bodian 2014). ATM Met1321Ile was observed at an allele frequency of 0.15% (28/18,854) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Met1321Ile 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 Met1321Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120136 SCV000084275 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000465561 SCV000547072 uncertain significance Ataxia-telangiectasia syndrome 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1321 of the ATM protein (p.Met1321Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs35184530, ExAC 0.08%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 133618). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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