ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.202A>G (p.Ile68Val) (rs35389822)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115148 SCV000185268 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115148 SCV000902983 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
Counsyl RCV000199503 SCV000791981 uncertain significance Ataxia-telangiectasia syndrome 2017-06-02 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000515328 SCV000611348 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000587881 SCV000149057 uncertain significance not provided 2018-01-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.202A>G at the cDNA level, p.Ile68Val (I68V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was seen in 1/2,399 control individuals and 0/4,112 breast cancer cases in a large meta-analysis of rare ATM variants and in at least one individual with familial pancreatic cancer (Tavtigian 2009, Chaffee 2017). This variant was also identified in an individual with cancer and in an individual undergoing multi-gene hereditary cancer panel testing (Petereit 2013, Mu 2016), but details of these individuals' personal and family histories were not provided. ATM Ile68Val 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 Ile68Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587881 SCV000694207 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The ATM c.202A>G (p.Ile68Val) variant involves the alteration of a conserved nucleotide. Ile68 is not conserved across species and is not located in a known functional domain; 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/102164 control chromosomes at a frequency of 0.0000294, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was identified in only one cancer patient reported in the literature, however, no clinical or co-segregation data was provided, thus its implication in this patients cancer diagnosis cannot be assessed (Petereit_2013). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000199503 SCV000254067 uncertain significance Ataxia-telangiectasia syndrome 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 68 of the ATM protein (p.Ile68Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs35389822, ExAC 0.004%). This variant has been reported in an individual affected with cancer (PMID: 24416720), and an unaffected individual (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 127344). 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 valine 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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