Submissions for variant NM_000051.4(ATM):c.2251-10T>G

gnomAD frequency: 0.00001  dbSNP: rs730881346

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159691	SCV000209697	pathogenic	not provided	2023-09-24	criteria provided, single submitter	clinical testing	Observed as a single heterozygous variant in individuals with breast, pancreatic, or other cancers (Decker et al., 2017; Hu et al., 2018; Abdel-Rahman et al., 2020); Functional studies demonstrate abnormal splicing: creation of a new splice acceptor site resulting in the addition of nine nucleotides and subsequent protein truncation (Telatar et al., 1998; Teraoka et al., 1999; External communication with Ambry Genetics); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as ATM IVS16-10T>G; This variant is associated with the following publications: (PMID: 28281021, 29922827, 16014569, 12497634, 10330348, 26681312, 16141195, 9463314, 27304073, 21792198, 28182994, 12673797, 9443866, 28779002, 12552559, 31447099, 35626031, 32081490, 34570182, 34539671, 10873394)
Invitae	RCV000161929	SCV000211913	pathogenic	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881346, gnomAD 0.002%). This variant has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 9443866, 9463314, 10330348, 10873394, 12552559, 26681312). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS16-10T>G or 2249ins9nt. ClinVar contains an entry for this variant (Variation ID: 181926). Studies have shown that this variant alters ATM gene expression (PMID: 9463314, 10873394, 21792198). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515310	SCV000611162	likely pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000161929	SCV000678106	likely pathogenic	Ataxia-telangiectasia syndrome	2017-02-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580644	SCV000682043	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -10 position of intron 14 of the ATM gene. Splice site prediction tools predict that this variant may create an alternative splice acceptor site. The use of this splice site is predicted to create a premature translation termination signal and is expected to result in an absent or non-functional protein product. Cell lines that are homozygous for this variant are reported to have undetectable ATM protein and autophosphorylation activity (PMID: 28182994). This variant (also known as IVS16-10T>G in the literature) has been reported in the homozygous state and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 9443866, 9463314, 10330348, 10873394, 12552559, 21792198, 34539671). Cells derived from some of these individuals have shown reduced or absent ATM protein levels and undetectable ATM kinase activity (PMID: 10873394, 21792198). This variant has also been reported in individuals affected with breast cancer and pancreatic cancer (PMID: 26681312, 28281021, 28779002, 29922827). This variant has been identified in 3/281524 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 Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000159691	SCV000805513	pathogenic	not provided	2016-01-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000161929	SCV001158080	pathogenic	Ataxia-telangiectasia syndrome	2018-12-27	criteria provided, single submitter	clinical testing	The ATM c.2251-10T>G variant (rs730881346), also known as IVS16-10T>G, is reported in the literature in multiple individuals with ataxia-telangiectasia, both in the homozygous state and in trans to other pathogenic variants (Becker-Catania 2000, Buzin 2003, Stankovic 1998, Telatar 1998). This variant has also been reported in an individual affected with breast cancer (Susswein 2016). The c.2251-10T>G variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 181926), and it is found on only three chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic acceptor splice site, leading to inclusion of nine nucleotides containing a premature stop codon. RNA studies from patient cells containing this variant support this effect on splicing (Teraoka 1999), and immunoblotting performed on cells homozygous for this variant indicate no detectable ATM variant present (Stankovic 1998, Wang 2017). Based on available information, this variant is considered to be pathogenic. References: Becker-Catania SG et al. Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity. Mol Genet Metab. 2000 Jun;70(2):122-33. Buzin CH et al. Comprehensive scanning of the ATM gene with DOVAM-S. Hum Mutat. 2003 Feb;21(2):123-31. Stankovic T et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-45. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Telatar M et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998 Jan;62(1):86-97. Teraoka SN et al. Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet. 1999 Jun;64(6):1617-31. Wang C et al. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib. Transl Oncol. 2017 Apr;10(2):190-196.
Ambry Genetics	RCV000580644	SCV001175711	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The c.2251-10T>G intronic pathogenic mutation results from a T to G substitution 10 nucleotides upstream from coding exon 14 in the ATM gene. This alteration has been reported in conjunction with a second, pathogenic mutation in multiple individuals diagnosed with ataxia-telangiectasia (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Teraoka SN et al. Am. J. Hum. Genet. 1999 June;64:1617-31; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Campbell C et al. Hum. Mutat. 2003 Jan;21:80-85; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31). In addition, this alteration has been identified in individuals diagnosed with breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies showed abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000161929	SCV001362540	pathogenic	Ataxia-telangiectasia syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2251-10T>G alters a conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. Two predict the variant abolishes a 3' acceptor site. Experimental evidence in support of these predictions demonstrated the variant to create a novel splice site and cause the insertion of 9 nucleotides eventually leading to truncation of the protein (Teraoka_1999). The variant allele was found at a frequency of 1.1e-05 in 275962 control chromosomes (gnomAD). c.2251-10T>G has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Reiman_2011, Buzin_2003, Becker-Catania_2000, Telatar_1998). The variant has also been reported in individuals affected with breast and pancreatic cancer (Hu_2018, Susswein_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12552559, 10330348, 10873394, 26681312, 21792198, 9443866, 28281021, 29922827, 28182994). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=9) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253609	SCV001429425	uncertain significance	Familial cancer of breast	2018-10-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000580644	SCV002536447	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	curation
Baylor Genetics	RCV001253609	SCV004206925	pathogenic	Familial cancer of breast	2023-10-11	criteria provided, single submitter	clinical testing