ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7999A>G (p.Met2667Val) (rs34099398)

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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 RCV000130136 SCV000184969 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416016 SCV000493557 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
Color RCV000130136 SCV000903238 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000416016 SCV000564664 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.7999A>G at the cDNA level, p.Met2667Val (M2667V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). In a case-control study, this variant was observed at similar frequencies in breast cancer cases (1/2531) and controls (1/2245) (Tavtigian 2009). This variant was also observed in an individual with colorectal cancer who harbored a second, reportedly pathogenic, ATM variant (Yurgelun 2017). ATM Met2667Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Met2667Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000474473 SCV000546996 uncertain significance Ataxia-telangiectasia syndrome 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 2667 of the ATM protein (p.Met2667Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with neurofibromatosis and breast cancer (Invitae). However, in that individual pathogenic alleles were also identified in NF1 and ATM, which suggests that this c.7999A>G variant was not the primary cause of disease. This variant has also been reported in an individual affected with colorectal cancer (PMID: 28135145), as well as in an individual with breast cancer and an unaffected control individual (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 141559). 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.

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