ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7592T>C (p.Met2531Thr) (rs587781365)

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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 RCV000129166 SCV000183899 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000656762 SCV000209644 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.7592T>C at the cDNA level, p.Met2531Thr (M2531T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). Tavtigian et al. (2009) reported this variant in one breast cancer patient in a meta-analysis of case-control studies. This variant was also observed in an individual with early-onset colorectal cancer, co-occurring with an MLH1 truncating variant, as well as in one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps and two individuals with pancreatic cancer (Yurgelun 2015, Pearlman 2017, Chaffee 2018). ATM Met2531Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Met2531Thr is located within the FAT domain (Stracker 2013). 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 Met2531Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195721 SCV000254148 uncertain significance Ataxia-telangiectasia syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2531 of the ATM protein (p.Met2531Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs587781365, ExAC 0.009%). This variant has been observed in individuals with breast cancer (PMID: 19781682) and pancreatic cancer (PMID: 28726808), as well as in an individual with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 140910). 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 threonine 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656762 SCV000344511 uncertain significance not provided 2016-08-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000656762 SCV000840962 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing
Color RCV000129166 SCV000910932 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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