ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4964C>A (p.Ser1655Tyr) (rs786201215)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163104 SCV000213613 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000486511 SCV000566497 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.4964C>A at the cDNA level, p.Ser1655Tyr (S1655Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCC>TAC). This variant was identified in an unaffected 44 year old female who underwent multi-gene cancer panel testing, and also harbored a CDH1 truncating variant (Huynh 2016). ATM Ser1655Tyr was not observed in large population cohorts (Lek 2016). Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Ser1655Tyr occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Ser1655Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000804749 SCV000944672 uncertain significance Ataxia-telangiectasia syndrome 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 1655 of the ATM protein (p.Ser1655Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an unaffected individual who underwent multi-gene cancer panel testing (PMID: 27064202). ClinVar contains an entry for this variant (Variation ID: 184002). 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 C15"). 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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