Submissions for variant NM_000051.4(ATM):c.3712_3716del (p.Leu1238fs)

dbSNP: rs786201675

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164077	SCV000214687	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	clinical testing	The c.3712_3716delTTATT pathogenic mutation, located in coding exon 24 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 3712 to 3716, causing a translational frameshift with a predicted alternate stop codon (p.L1238Kfs*6). This mutation has been reported in multiple homozygous and compound heterozygous individuals with ataxia-telangiectasia (A-T) (Vorechovský I et al. Eur. J. Hum. Genet. 1996;4:352-5; Broeks A et al. Hum. Mutat. 1998;12:330-7; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar;20:305-12; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174; Berland A et al. J Allergy Clin Immunol, 2019 01;143:325-334.e2). Of note, this alteration is also designated as 3709del5 and 3711del5 in published literature. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164077	SCV000266016	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000222105	SCV000278822	pathogenic	not provided	2024-03-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed heterozygous in individuals with ATM-related cancers (PMID: 30303537, 31432501); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3711del5 and c.3705delTTTTA; This variant is associated with the following publications: (PMID: 21933854, 21445571, 16238588, 27664052, 34234304, 32782288, 29922827, 22071889, 10817650, 9043869, 23091097, 9792409, 27528516, 26556299, 30303537, 31432501, 31589614, 33436325, 35312039, 12815592)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459956	SCV000546745	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1238Lysfs*6) 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, chronic lymphocytic leukemia, or bladder cancer, sarcoma, and polyposis (PMID: 21665257, 21933854, 22071889, 26845104, 27528516). ClinVar contains an entry for this variant (Variation ID: 184764). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164077	SCV000904683	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-21	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 25 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 the homozygous state or compound heterozygous state with a second ATM mutation in individuals affected with ataxia telangiectasia (PMID: 9792409, 10817650, 12815592, 21665257, 22071889, 27528516). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000459956	SCV000916544	pathogenic	Ataxia-telangiectasia syndrome	2017-10-30	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.3712_3716delTTATT (p.Leu1238LysfsX6) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 241134 control chromosomes (gnomAD). Multiple publications have cited the variant in homozygote and compound heterozygote A-T pts. In addition, multiple clinical diagnostic laboratories classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000459956	SCV002583660	pathogenic	Ataxia-telangiectasia syndrome	2022-08-29	criteria provided, single submitter	clinical testing	PVS1 PS3 PM2
Fulgent Genetics, Fulgent Genetics	RCV002492652	SCV002777531	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-11-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001554336	SCV004207584	pathogenic	Familial cancer of breast	2024-02-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001554336	SCV004933273	pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000222105	SCV005090247	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000459956	SCV001458188	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554336	SCV001774806	pathogenic	Familial cancer of breast	2021-08-07	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000222105	SCV003840126	pathogenic	not provided	2022-07-29	no assertion criteria provided	clinical testing	DNA sequence analysis of the ATM gene demonstrated a 5 base pair deletion in exon 25, c.3712_3716del. This sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the change, p.Leu1238Lysfs*6. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. The c.3712_3716del sequence change has not been described in population databases such as ExAC and gnomAD. The c.3712_3716del sequence change has previously been described in the compound heterozygous state in individuals with ataxia-telangiectasia (PMID: 22071889, 27528516). This variant has also been identified in the germline heterozygous state in an individual with esophagogastric adenocarcinoma and in an individual with familial pancreatic cancer (PMID: 26556299, 31432501). Similar frameshift variants in this region have also been described in individuals with ATM-related disorders and have been described as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004739515	SCV005360180	pathogenic	ATM-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The ATM c.3712_3716del5 variant is predicted to result in a frameshift and premature protein termination (p.Leu1238Lysfs*6). This variant has been reported in multiple individuals with ataxia-telangiectasia (A-T) (examples, Carranza et al. 2016. PubMed ID: 27664052; Li et al. 2000. PubMed ID: 10817650; Marelli et al. 2016. PubMed ID: 27528516). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184764/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.