ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3601T>A (p.Phe1201Ile) (rs576884305)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567287 SCV000660510 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567287 SCV000682150 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726329 SCV000343819 uncertain significance not provided 2016-08-17 criteria provided, single submitter clinical testing
GeneDx RCV000726329 SCV000566555 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.3601T>A at the cDNA level, p.Phe1201Ile (F1201I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTT>ATT). This variant has been reported in at least one individual with early-onset breast cancer who underwent multi-gene hereditary cancer panel testing (Maxwell 2014). ATM Phe1201Ile was not observed at significant allele frequency in large population cohorts (Lek 2016). This variant is located within the beta-adaptin interaction region (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 Phe1201Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204970 SCV000261666 uncertain significance Ataxia-telangiectasia syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 1201 of the ATM protein (p.Phe1201Ile). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is present in population databases (rs576884305, ExAC 0.02%). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 220809). 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. 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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