Submissions for variant NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)

gnomAD frequency: 0.00001  dbSNP: rs139770721

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212037	SCV000209757	pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000159742	SCV000214152	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000167946	SCV000218594	pathogenic	Ataxia-telangiectasia syndrome	2023-12-25	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000167946	SCV000220988	likely pathogenic	Ataxia-telangiectasia syndrome	2014-12-23	criteria provided, single submitter	literature only
Color Diagnostics, LLC DBA Color Health	RCV000159742	SCV000682303	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167946	SCV000694316	pathogenic	Ataxia-telangiectasia syndrome	2015-12-07	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709711	SCV000839886	pathogenic	Familial cancer of breast	2018-01-30	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000762824	SCV000893182	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000212037	SCV000928203	pathogenic	not provided	2019-02-05	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000709711	SCV001367968	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PS3_MOD, PM3_VSTR
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000709711	SCV001499611	likely pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001706063	SCV001934218	likely pathogenic	Adenocarcinoma	2020-10-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000167946	SCV002020687	pathogenic	Ataxia-telangiectasia syndrome	2019-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212037	SCV003916783	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ATM: PM3:Strong, PS3, PM2, PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000709711	SCV004176013	pathogenic	Familial cancer of breast	2023-11-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3,PP3
Baylor Genetics	RCV000709711	SCV004210046	pathogenic	Familial cancer of breast	2023-08-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917547	SCV004732114	pathogenic	ATM-related condition	2023-12-15	criteria provided, single submitter	clinical testing	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.
CZECANCA consortium	RCV001391204	SCV001593147	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001657897	SCV001877089	likely pathogenic	Breast carcinoma		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000709711	SCV002588955	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162671	SCV002758103	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research