ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3743A>G (p.Tyr1248Cys) (rs766226370)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471000 SCV000546818 uncertain significance Ataxia-telangiectasia syndrome 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1248 of the ATM protein (p.Tyr1248Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs766226370, ExAC 0.004%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407541). 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 disruptive, 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.
GeneDx RCV000485361 SCV000564630 uncertain significance not provided 2016-11-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.3743A>G at the cDNA level, p.Tyr1248Cys (Y1248C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr1248Cys 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 Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr1248Cys occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether ATM Tyr1248Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573918 SCV000660531 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000573918 SCV000904607 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-20 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory,University of Pittsburgh Medical Center RCV001249850 SCV001424012 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-02 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (A>G) that results in a tyrosine to cysteine amino acid change at residue 1248 of the ATM protein. This is a previously reported (ClinVar), rare variant which has been observed in the ExAC population database at a frequency of 0.00001885 (2/106078 alleles). The protein change does not lie in any known functional domain of the ATM protein. Tyrosine at position 1248 of the ATM protein is highly conserved, being present in 61/62 mammalian species examined. Multiple computational tools queried predict that this protein change is likely damaging to protein structure and/or function; however, no functional studies have been performed to confirm these predictions, to our knowledge. Due to the lack of sufficient information available at this time, it is not possible to determine if this is a benign or pathogenic variant. Thus, we consider it to be a variant of uncertain significance.

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