ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3352A>G (p.Thr1118Ala) (rs572564322)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211998 SCV000209727 uncertain significance not provided 2018-11-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.3352A>G at the cDNA level, p.Thr1118Ala (T1118A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has been reported in at least one individual with breast cancer (Decker 2017). ATM Thr1118Ala was observed at an allele frequency of 0.16% (50/30774) in individuals of South Asian ancestry in large population cohorts (Lek 2016). ATM Thr1118Ala is located in the beta-adaptin interaction domain (Tavtigian 2009). 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 Thr1118Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159715 SCV000217389 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000335065 SCV000367045 uncertain significance Ataxia-telangiectasia syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000335065 SCV000546834 uncertain significance Ataxia-telangiectasia syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1118 of the ATM protein (p.Thr1118Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs572564322, ExAC 0.2%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181948). 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 alanine 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, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000335065 SCV000798489 uncertain significance Ataxia-telangiectasia syndrome 2018-03-12 criteria provided, single submitter clinical testing
Color RCV000159715 SCV000910962 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing

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