Submissions for variant NM_000051.4(ATM):c.6452G>C (p.Arg2151Thr)

dbSNP: rs2136222746

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001977826	SCV002265312	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with threonine at codon 2151 of the ATM protein (p.Arg2151Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 44, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479381	SCV004223334	uncertain significance	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6452G>C (p.Arg2151Thr) results in a non-conservative amino acid change located in the PIK-related kinase, FAT (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. This variant also falls at the last nucleotide of exon 44, which is within the consensus splice region for this exon. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the 5' canonical splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248184 control chromosomes. c.6452G>C has been reported at a homozygous state in at-least one individual affected with Ataxia-telangiectasia (example, Amirifar_2022, Amirifar_2021, Azizi_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34628594, 33547824, 36790564). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.