Submissions for variant NM_000051.4(ATM):c.8596C>T (p.Leu2866Phe)

dbSNP: rs368666328

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217814	SCV000274976	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.L2866F variant (also known as c.8596C>T), located in coding exon 58 of the ATM gene, results from a C to T substitution at nucleotide position 8596. The leucine at codon 2866 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved through mammals. 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.
GeneDx	RCV000236111	SCV000293514	uncertain significance	not provided	2015-11-17	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8596C>T at the cDNA level, p.Leu2866Phe (L2866F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu2866Phe 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 Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Leu2866Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within PI3K/PI4K domain and region of interaction with TP53 (Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Leu2866Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465062	SCV000546717	uncertain significance	Ataxia-telangiectasia syndrome	2024-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2866 of the ATM protein (p.Leu2866Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 231206). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Baylor Genetics	RCV004567551	SCV005057003	uncertain significance	Familial cancer of breast	2024-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701285	SCV005203026	uncertain significance	not specified	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8596C>T (p.Leu2866Phe) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five 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 250040 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.8596C>T in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 231206). Based on the evidence outlined above, the variant was classified as uncertain significance.