Submissions for variant NM_000051.4(ATM):c.756_757del (p.Cys252_Glu253delinsTer)

dbSNP: rs876659003

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222737	SCV000274943	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-14	criteria provided, single submitter	clinical testing	The c.756_757delTG pathogenic mutation, located in coding exon 6 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 756 to 757, causing a translational frameshift with a predicted alternate stop codon (p.C252*). This alteration has been reported (labeled as 755delG) in the literature in an Italian ataxia telangiectasia (A-T) family (Gilad S et al, Hum. Mol. Genet. 1996 Apr; 5(4):433-9). In addition to the clinical data presented in the literature, 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.
Counsyl	RCV000409635	SCV000487283	likely pathogenic	Ataxia-telangiectasia syndrome	2016-11-09	criteria provided, single submitter	clinical testing
Invitae	RCV000409635	SCV000749096	pathogenic	Ataxia-telangiectasia syndrome	2023-07-30	criteria provided, single submitter	clinical testing	This variant is also known as 755delGT. ClinVar contains an entry for this variant (Variation ID: 231178). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835). This sequence change creates a premature translational stop signal (p.Cys252*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409635	SCV000916613	pathogenic	Ataxia-telangiectasia syndrome	2018-12-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.756_757delTG (p.Cys252X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1027_1030delGAAA/p.Glu343fsX2, c.1139_1142dupACAG/p.Ser381fsX27). The variant was absent in 245832 control chromosomes. c.756_757delTG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Gilad_996a, Sun_2002, Heinrich_2006, Prodosmo_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence showing that this variant may lead to loss of protein expression (Sun_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003316212	SCV004019236	pathogenic	Familial cancer of breast	2023-02-08	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.