ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5053A>G (p.Thr1685Ala) (rs879254205)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236018 SCV000293829 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.5053A>G at the cDNA level, p.Thr1685Ala (T1685A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr1685Ala 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. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr1685Ala occurs at a position that is conserved across species and is not located in a known functional domain (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 Thr1685Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571535 SCV000660562 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000801609 SCV000941393 uncertain significance Ataxia-telangiectasia syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1685 of the ATM protein (p.Thr1685Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 246323). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000801609 SCV001138512 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249855 SCV001424017 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-22 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (A>G) that results in a threonine to alanine amino acid change at residue 1685 in the ATM protein. The variant is rare, and is absent from the ExAC database. It is present in the gnomAD database in 1/245964 alleles (0.0004066%). The variant is not, to our knowledge, mentioned in the literature among cancer patients or healthy controls. The variant does not lie in a known ATM functional domain. The threonine residue at position 1685 is highly conserved among vertebrate species, and is present in 91/92 vertebrates analyzed. In silico prediction models are inconsistent in their predictions on whether or not this change will negatively affect protein function, and no studies on the effect of this variant on protein function have been performed. Given the lack of information about this variant, it is unclear whether it is pathogenic or benign. Thus, it is a variant of uncertain significance.

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