Submissions for variant NM_000051.4(ATM):c.6283C>A (p.Leu2095Ile)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002368701	SCV002657071	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-22	criteria provided, single submitter	clinical testing	The p.L2095I variant (also known as c.6283C>A), located in coding exon 42 of the ATM gene, results from a C to A substitution at nucleotide position 6283. The leucine at codon 2095 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003500730	SCV004308076	uncertain significance	Ataxia-telangiectasia syndrome	2023-07-26	criteria provided, single submitter	clinical testing	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 1752611). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2095 of the ATM protein (p.Leu2095Ile).
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV002368701	SCV005901815	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-18	criteria provided, single submitter	clinical testing	PM2_Supporting, BP4 c.6283C>A located in exon 43 of the ATM gene, is predicted to result in the substitution of leucine by isoleucine at codon 2095, p.(Leu2095Ile). It is not present in the population database gnomAD v2.1.1 (non-cancer, exome only subset) (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.135) suggests that it does not affect the protein function (BP4). To our knowledge, functional studies have not been reported for this variant. In addition, the variant was also identified in the ClinVar database (2x uncertain significance) but is not present in LOVD database. Based on currently available information, the variant c.6283C>A is classified as an uncertain significance variant according to ClinGen-ATM Guidelines version v1.1.