ClinVar Genomic variation as it relates to human health

Variant summary: ATM c.7181C>T (p.Ser2394Leu) results in a non-conservative amino acid change located in the PIK-related kinase (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 251332 control chromosomes. c.7181C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Ataxia-Telangiectasia (example, Lin_2015) and in settings of multigene panel testing for cancers (example, Susswein_2016). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of ATM-kinase activity (Austen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 19431188, 31843900, 34848827, 26677768, 26681312, 33119476). ClinVar contains an entry for this variant (Variation ID: 127437). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Observed with a pathogenic variant on the opposite allele (in trans) in a patient with atypical ataxia telangiectasia (PMID: 26677768); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19431188, 26681312, 32647791, 18573109, no PMID, 26677768, 23532176)

This missense variant replaces serine with leucine at codon 2394 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant protein displays no detectable kinase activity in response to ionizing radiation (PMID: 18573109, 19431188). This variant has been reported in trans with a pathogenic ATM truncating variant in an individual affected with ataxia telangiectasia (PMID: 26677768). Cells derived from this individual expressed full-length ATM protein, but showed reduced X-irradiation (XR)-induced phosphorylation of CHEK2 and XR-induced gamma H2A.X nuclear puncta, suggesting little or no ATM kinase activity (PMID: 26677768). 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.

The second sequence change, c.7181C>T, in exon 49 results in an amino acid change, p.Ser2394Leu. The p.Ser2394Leu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser2394Leu substitution. This particular amino acid change has been described in the literature in one female patient with Ataxia-telangiectasia along with another pathogenic change (Lin et al., 2015). In vitro expression studies have shown that the resulting p.Ser2394Leu protein has absent ATM kinase activity (Barone et al., 2009 and Austen et al., 2008). This sequence change has not been described in the population databases (ExAC and gnomAD). These collective evidences indicate that this sequence change is likely pathogenic. This sequence change was identified with another pathogenic ATM variant in a patient.

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2394 of the ATM protein (p.Ser2394Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 26677768). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127437). 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: 18573109, 19431188, 26677768). 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.

The p.S2394L variant (also known as c.7181C>T), located in coding exon 48 of the ATM gene, results from a C to T substitution at nucleotide position 7181. The serine at codon 2394 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in trans with a truncating mutation in a patient with ataxia telangiectasia (Lin L et al. Stem Cell Reports. 2015 Dec; 5(6):1097-108). This alteration was identified with a truncating mutation in another individual with ataxia telangiectasia, however phase was not documented (Kim J et al. Nature, 2023 Jul;619:828-836). In vitro analysis indicate this variant has absent ATM kinase activity (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30; Austen B et al. Br. J. Haematol. 2008 Sep; 142(6):925-33). This alteration has also been detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med 2018 04;7(4):1349-1358). 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.