ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8129A>G (p.Lys2710Arg) (rs587782001)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130416 SCV000185278 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130416 SCV000911183 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000485472 SCV000569236 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.8129A>G at the cDNA level, p.Lys2710Arg (K2710R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has been observed in at least one individual with a personal history of colorectal cancer (Pearlman 2016). ATM Lys2710Arg 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 Lys2710Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000547885 SCV000622803 uncertain significance Ataxia-telangiectasia syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 2710 of the ATM protein (p.Lys2710Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 141775). 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 arginine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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