ClinVar Genomic variation as it relates to human health

The c.5858C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1953 (p.Thr1953Ile). This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 18634022, 26896183). This variant is absent from gnomAD v2.1.1. Additionally, experimental studies showed that this variant impacts ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_supporting, PS3_supporting, PP3)

The p.T1953I variant (also known as c.5858C>T) is located in coding exon 38 of the ATM gene. This alteration results from a C to T substitution at nucleotide position 5858. The threonine at codon 1953 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in conjunction with a pathogenic ATM variant, c.8786+1G>A, in one individual from the UK diagnosed with ataxia-telangiectasia (AT) (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). This alteration was also reported in conjunction with another ATM alteration, p.W2109G, in an individual diagnosed with atypical AT who presented with truncal ataxia and telangiectasia since childhood (Mitui, M et al. Hum Mutat. 2009 Jan;30(1):12-21). Functional studies performed by Mitui et al. showed reduced expression and intermediate radiosensitivity, and led the authors to conclude that this alteration is most likely a "kinase-impaired" protein. This alteration has been identified in at least one patient with a personal and family history of breast, ovarian cancer, and prostate cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Variant summary: ATM c.5858C>T (p.Thr1953Ile) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251084 control chromosomes. c.5858C>T has been reported in the literature in compound heterozygosity with other ATM variants in at-least two individuals affected with Ataxia-Telangiectasia (examples, Mitui_2009, Jackson_2016) and as a VUS in settings of multigene panel testing in one individual affected with breast cancer (example, Tung_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, it was not possible to definitively demonstrate whether the lack of ATM functions was due to reduced ATM protein or leaky expression of a "kinase-impaired" protein (Mitui_2009). The following publications have been ascertained in the context of this evaluation (PMID: 26896183, 18634022, 25186627). ClinVar contains an entry for this variant (Variation ID: 141721) and at-least three peer submitters have classified the variant as Likely Pathogenic, two of whom cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, pending additional clinical evidence supporting an unequivocal association with Ataxia-Telangiectasia, the variant was classified as likely pathogenic.

The ATM c.5858C>T (p.Thr1953Ile) variant has been reported in the published literature in individuals with breast cancer (PMID: 25186627 (2017)) and prostate cancer (PMID: 31214711 (2020)). This variant has been identified in individuals with ataxia-telangiectasia (AT) who also carried other pathogenic ATM variants (PMID: 18634022 (2009), 26896183 (2016)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 18634022 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1953 of the ATM protein (p.Thr1953Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or ATM-related cancers (PMID: 18634022, 25186627, 26896183, 31214711). ClinVar contains an entry for this variant (Variation ID: 141721). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 18634022). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces threonine with isoleucine at codon 1953 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. An in vitro functional study has shown that this variant results in significantly reduced ATM protein expression and kinase activity (PMID: 18634022). This variant has been reported in a 46-year-old woman affected with breast cancer (PMID: 25186627) and an individual affected with prostate cancer (PMID: 31214711). This variant has also been observed in the compound heterozygous state with a known pathogenic ATM variant in a 3-year-old child affected with autosomal recessive classic ataxia-telangiectasia, indicating that this variant contributes to disease (PMID: 26896183). In addition, this variant has been observed in an adult affected with mild ataxia-telangiectasia phenotype, who also carried a variant of uncertain significance, p.Trp2109Gly, in the same gene (PMID: 18634022). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.