Submissions for variant NM_000051.4(ATM):c.8575TCT[1] (p.Ser2860del)

dbSNP: rs786203976

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221464	SCV002499298	pathogenic	Familial cancer of breast	2022-03-16	reviewed by expert panel	curation	The ATM c.8578_8580delTCT (p.S2860del) variant has been observed in the compound heterozygous state (presumed) in two individuals affected with ataxia-telangiectasia and it has also been observed in the compound heterozygous state (confirmed) in an individual affected with generalized dystonia, without classical AT features (PMIDs: 22213089, 31920950 PM3_verystrong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In silico structural impact predictors (Provean, -11.099) predict that this alteration is deleterious (PP3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
Ambry Genetics	RCV000167512	SCV000218370	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	The c.8578_8580delTCT variant is located in coding exon 57 of the ATM gene. This variant results from an in-frame TCT deletion at nucleotide positions 8578 to 8580, causing the removal of a highly-conserved serine residue at codon 2860. This variant has been detected in trans with a second ATM pathogenic variant in a patient with generalized dystonia (Kuhm C et al. J Neurol, 2015 Mar;262:768-70). In addition, this variant has been observed in two unrelated patients with ataxia-telangiectasia (A-T), each harboring a second ATM pathogenic variant (Verhagen MM et al. Neurology, 2009 Aug;73(6):430-7; Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). Functional studies have revealed low expression of ATM protein in A-T patient cell lines, without detectable kinase activity (Reiman A et al. Br J Cancer, 2011 Aug;105:586-91; Verhagen MM et al. Hum Mutat, 2012 Mar;33:561-71). Based on internal structural analysis, S2860del is predicted to disrupt the ATM kinase domain to a higher degree than nearby pathogenic variants in the same domain (Bareti D et al. Sci Adv, 2017 May;3(5):e1700933). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000003154	SCV000546693	likely pathogenic	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This variant, c.8578_8580del, results in the deletion of 1 amino acid(s) of the ATM protein (p.Ser2860del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786203976, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 7792600, 9792409, 19535770, 21792198, 22213089, 25572163). 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: 3018). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
GeneDx	RCV000480186	SCV000568341	likely pathogenic	not provided	2022-06-09	criteria provided, single submitter	clinical testing	Observed multiple times with a pathogenic ATM variant in patients with dystonia or classic ataxia telangiectasia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) alleles in some cases (Verhagen et al., 2009; Reiman et al., 2011; Verhagen et al., 2012; Kuhm et al., 2015; van Os et al., 2017; Pogoda et al., 2019); Identified in the heterozygous state in individuals with pancreatic cancer (Ding et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7792600, 31920950, 19535770, 28194276, 28126470, 30504431, 28779002, 22213089, 21792198, 25572163, 34771661, 15279808, 23532176, 33127389)
Color Diagnostics, LLC DBA Color Health	RCV000167512	SCV000682502	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid in the kinase domain of the ATM protein. This variant has been reported in individuals affected with ataxia telangiectasia, including in the compound heterozygous state with an additional pathogenic ATM variant (PMID: 7792600, 8845835, 9259193, 9792409, 19535770, 21792198, 22213089). Cells derived from two of these individuals have shown the presence of ATM protein but no detectable ATM kinase activity (PMID: 21792198, 22213089). This variant has also been reported in the compound heterozygous state in an individual affected with dystonia (PMID: 25572163, 31920950) and in the heterozygous state in an individual affected with pancreatic cancer (PMID: 33127389). This variant has been identified in 1/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV002221464	SCV004212229	pathogenic	Familial cancer of breast	2022-08-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221464	SCV004930405	likely pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19535770, 22213089, 21792198, 9792409].
OMIM	RCV000003154	SCV000023312	pathogenic	Ataxia-telangiectasia syndrome	1995-06-23	no assertion criteria provided	literature only