ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3295G>T (p.Asp1099Tyr) (rs372966951)

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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 RCV000574828 SCV000667925 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000574828 SCV000687464 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
GeneDx RCV000482385 SCV000571144 uncertain significance not provided 2017-02-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.3295G>T at the cDNA level, p.Asp1099Tyr (D1099Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp1099Tyr 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 Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Asp1099Tyr occurs at a position that is not conserved and is located in the beta-adaptin interaction domain (Tavtigian 2009). 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 Asp1099Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000546836 SCV000622404 uncertain significance Ataxia-telangiectasia syndrome 2017-10-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 1099 of the ATM protein (p.Asp1099Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 421832). 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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