Submissions for variant NM_000051.4(ATM):c.138_141del (p.His46fs)

dbSNP: rs786203370

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166647	SCV000217451	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-17	criteria provided, single submitter	clinical testing	The c.138_141delTTCA pathogenic mutation, located in coding exon 2 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 138 to 141, causing a translational frameshift with a predicted alternate stop codon (p.H46Qfs*9). 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.
GeneDx	RCV000235307	SCV000293427	pathogenic	not provided	2018-10-26	criteria provided, single submitter	clinical testing	This deletion of four nucleotides in ATM is denoted c.138_141delTTCA at the cDNA level and p.His46GlnfsX9 (H46QfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GGCA[delTTCA]GATT. The deletion causes a frameshift which changes a Histidine to a Glutamine at codon 46, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.138_141delTTCA, also reported as ATM 136del4 using alternate nomenclature, has been reported with a second ATM variant in two siblings and at least one other individual with Ataxia-telangiectasia (Stankovic 1998, Jacquemin 2012). Functional studies on cell lines derived from these individuals found decreased ATM protein levels, impaired phosphorylation after exposure to ionizing radiation, and absent kinase activity (Stewart 2001, Jacquemin 2012). Based on current evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690803	SCV000818530	pathogenic	Ataxia-telangiectasia syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His46Glnfs*9) 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 ataxia-telangiectasia (PMID: 9463314, 22071889). This variant is also known as c.138_141del4 and 136del4nt. ClinVar contains an entry for this variant (Variation ID: 186975). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004019986	SCV004930577	pathogenic	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000690803	SCV001461808	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004552926	SCV004708687	pathogenic	ATM-related disorder	2023-12-16	no assertion criteria provided	clinical testing	The ATM c.138_141delTTCA variant is predicted to result in a frameshift and premature protein termination (p.His46Glnfs*9). This variant along with a second variant in this gene was reported in two individuals with ataxia telangiectasia, who also have personal history of T-cell lymphoma (reported as 136del4nt in Table 1 and Table 4, Stankovic et al 1998. PubMed ID: 9463314; Jacquemin et al. 2011. PubMed ID: 22071889). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ATM are expected to be pathogenic. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/186975/). This variant is interpreted as pathogenic.