ClinVar Genomic variation as it relates to human health

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 41 of the ATM gene and replaces arginine with lysine at codon 2032 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies using carrier-derived RNA have shown that this variant causes the skipping of exon 41 (also known as exon 43 in the literature), creating a premature translation stop signal (PMID: 9443866, 9887333, 10980530). The aberrant transcript is expected to result in an absent or non-functional protein product. Functional cytometric analysis of cells from individuals carrying this variant and affected with chronic lymphocytic leukemia showed decreased kinase activity (PMID: 36029002). This variant has been described as a recurrent mutation in the Polish population (PMID: 9443866, 16266405) and has been reported in many individuals affected with ataxia-telangiectasia (PMID: 9443866, 9887333, 10330348, 10817650, 10980530, 16266405, 25614872, 27159176) or adult-onset focal dystonia (PMID: 37445923). This variant has also been reported in individuals affected breast cancer, prostate cancer, pancreatic cancer or gastric cancer (PMID: 22585167, 26506520, 29678143, 31012270, 34377931). In a large international case-control study, this variant was reported in 9/60466 breast cancer cases and 4/53461 controls (OR=1.989, 95%CI 0.613 to 6.461, p-value=0.279; PMID: 33471991). This variant has been identified in 7/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The c.6095G>A pathogenic mutation (also known as p.R2032K), located in coding exon 40 of the ATM gene, results from a G to A substitution at nucleotide position 6095. The amino acid change results in arginine to lysine at codon 2032, an amino acid with highly similar properties. This alteration has been described as a founder mutation in the Polish population and has been detected in conjunction with a second mutation in numerous probands with ataxia-telangiectasia (A-T) (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64. Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Beier R et al. Bone Marrow Transplant. 2016 09;51:1271-4). This mutation has also been reported in high-risk breast cancer cohorts (Schubert S et al. Int. J. Cancer 2018 Nov; Podralska M et al. Mol Genet Genomic Med 2014 Nov;2(6):504-11). This change occurs in the highly-conserved last base pair of coding exon 40, which makes it likely to have some effect on normal mRNA splicing. RT-PCR analysis performed on RNA isolated from an A-T individual with this alteration was reported to result in exon skipping (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have shown the same abnormal splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This c.6095G>A (p.R2032K) variant in the ATM gene has been reported in multiple Ataxia-telangiectasia (AT) patients with significantly higher prevalence [PMID: 10980530, 15390180,16266405] than that observed as extremely low in general population according to gnomad database. This variant, in trans with other deleterious variants, has been reported in AT patients [PMID: 27159176, 25614872]. Functional studies showed that this mutant causes abnormal splicing and loss of expression of ATM proteins [PMID: 9887333, 10330348]. Multiple in silico predictions suggest this arginine to lysine is deleterious, while the c.6095G>A change might affect the splicing of messenger RNA as the last nucleotide on exon 41. Based upon above evidences, this c.6095G>A (p.R2032K) variant in the ATM gene is classified as pathogenic.

PS3_MOD, PM3_VSTR

Alters the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and published functional studies and splice predictors support a deleterious effect (Telatar et al., 1998); Observed in the heterozygous state in individuals with ATM-related and other cancers (Thorstenson et al., 2003; Roberts et al., 2012; Huang et al., 2015; Yurgelun et al., 2015; Podralska et al., 2018; Waszak et al., 2018; Schubert et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15390180, 32875559, 28888541, 31921190, 20153123, 22585167, 12810666, 10817650, 10980530, 25980754, 26506520, 27878467, 29678143, 9443866, 10330348, 16266405, 27159176, 25614872, 9887333, 29753700, 30426508, 30772474, 23532176, 29625052, 31447099, 33077847, 34522244, 29922827, 34308104)

Criteria applied: PVS1,PM3,PP3

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2032 of the ATM protein (p.Arg2032Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs139770721, gnomAD 0.006%). This missense change has been observed in individuals with ataxia-telangiectasia, pancreatic cancer, or gastric cancer (PMID: 9887333, 10330348, 10980530, 16266405, 22585167, 25614872, 26506520, 27159176). ClinVar contains an entry for this variant (Variation ID: 181974). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 41 (also referred to as exon 43) and introduces a premature termination codon (PMID: 9887333; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16266405]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 9887333, 10330348].

ATM: PM3:Strong, PS3, PM2, PP3

The ATM c.6095G>A variant is predicted to result in the amino acid substitution p.Arg2032Lys. Of note, this variant occurs at the last nucleotide of the exon and is predicted to significantly weaken the donor splice site (Alamut Visual Plus v1.6.1) and exon skipping was observed in analyses from patient lymphocytes (Sandoval et al 1999. PubMed ID: 9887333). This variant has been observed in the compound heterozygous or homozygous state in individuals with ataxia telangiectasia (Sandoval. 1999. PubMed ID: 9887333; Teraoka et al. 1999. PubMed ID: 10330348; Mitui et al. 2005. PubMed ID: 16266405). The c.6095G>A variant has also been reported in the heterozygous state in several individuals with pancreatic cancer, gastric cancer, prostate cancer, and breast cancer (Roberts et al. 2012. PubMed ID: 22585167; Huang et al. 2015. PubMed ID: 26506520; Table 1, Wokołorczyk D et al 2020. PubMed ID: 32875559; Schubert S et al 2019. PubMed ID: 30426508). This variant was reported as a germline variant in a patient with chronic lymphocytic leukemia (Table S2. Petrackova et al. 2022. PubMed ID: 36029002). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is reported as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/181974/). This variant is interpreted as pathogenic.