ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2655A>T (p.Leu885Phe) (rs730881351)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159700 SCV000209710 uncertain significance not provided 2017-03-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.2655A>T at the cDNA level, p.Leu885Phe (L885F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu885Phe was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Leu885Phe occurs at a position that is conserved across species 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 Leu885Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000456359 SCV000546802 uncertain significance Ataxia-telangiectasia syndrome 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 885 of the ATM protein (p.Leu885Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181934). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000565271 SCV000665642 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-23 criteria provided, single submitter clinical testing The p.L885F variant (also known as c.2655A>T), located in coding exon 17 of the ATM gene, results from an A to T substitution at nucleotide position 2655. The leucine at codon 885 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Integrated Genetics/Laboratory Corporation of America RCV001251294 SCV001426831 uncertain significance not specified 2020-07-30 criteria provided, single submitter clinical testing Variant summary: ATM c.2655A>T (p.Leu885Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2655A>T in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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