Submissions for variant NM_000051.4(ATM):c.2720_2723del (p.Leu906_Cys907insTer)

dbSNP: rs786202695

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165633	SCV000216369	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-14	criteria provided, single submitter	clinical testing	The c.2720_2723delGTGT pathogenic mutation, located in coding exon 17 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 2720 to 2723, causing a translational frameshift with a predicted alternate stop codon (p.C907*). This alteration was previously reported in a cohort of 37 patients with a clinical diagnosis of ataxia telangiectasia (A-T) (Li A, Am. J. Med. Genet. 2000 May; 92(3):170-7). It has also been described in two unrelated Italian families with A-T that share the same haplotype, suggesting that it is a rare founder mutation (Chessa L, et al. Ann. Hum. Genet. 2009 Sep; 73(Pt 5):532-9). Of note, this alteration has also been designated as 2720_2723delTGTG in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genetic Services Laboratory, University of Chicago	RCV000193120	SCV000246614	pathogenic	Ataxia-telangiectasia syndrome	2015-07-17	criteria provided, single submitter	clinical testing
Invitae	RCV000193120	SCV000282909	pathogenic	Ataxia-telangiectasia syndrome	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys907*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with chronic lymphocytic leukemia and ataxia-telangiectasia (PMID: 10817650, 21933854). ClinVar contains an entry for this variant (Variation ID: 186103). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165633	SCV001339387	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 18 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 10817650, 19691550). This variant has not been identified 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.
Baylor Genetics	RCV003468749	SCV004212087	pathogenic	Familial cancer of breast	2023-02-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468749	SCV004932152	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Natera, Inc.	RCV000193120	SCV001452049	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing