ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6420C>A (p.Phe2140Leu) (rs587780635)

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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 RCV000574605 SCV000660477 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 RCV000574605 SCV000687695 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
GeneDx RCV000236625 SCV000292475 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.6420C>A at the cDNA level, p.Phe2140Leu (F2140L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has been observed in at least one individual who underwent multi-gene hereditary cancer panel testing (Mu 2016). ATM Phe2140Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Phe2140Leu occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). 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 Phe2140Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000122875 SCV000166133 uncertain significance Ataxia-telangiectasia syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 2140 of the ATM protein (p.Phe2140Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. 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: 135771). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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