ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8805G>A (p.Met2935Ile) (rs772621438)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561470 SCV000672700 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000484203 SCV000570412 uncertain significance not provided 2016-05-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.8805G>A at the cDNA level, p.Met2935Ile (M2935I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). ATM Met2935Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. However it was identified in 1/2245 controls and was absent from 2531 breast cancer cases in a meta analysis of case-control studies (Tavtigian 2009). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Met2935Ile occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the PI3/PI4 kinase domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Met2935Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467173 SCV000546958 uncertain significance Ataxia-telangiectasia syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 2935 of the ATM protein (p.Met2935Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs772621438, ExAC 0.03%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407626). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; 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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