Submissions for variant NM_000051.4(ATM):c.2284_2285del (p.Leu762fs)

dbSNP: rs587781658

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129801	SCV000184612	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-03	criteria provided, single submitter	clinical testing	The c.2284_2285delCT pathogenic mutation, located in coding exon 14 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 2284 to 2285, causing a translational frameshift with a predicted alternate stop codon (p.L762Vfs*2). This mutation has been reported in either a homozygous or compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (AT) (Byrd PJ et al. Hum. Mol. Genet. 1996 Jan;5:145-9; Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Kraus M et al. J Clin Immunol, 2014 Jul;34:561-72; Yu H et al. J. Allergy Clin. Immunol. 2016 Oct;138:1142-1151.e2). This mutation has also been reported in a heterozygous state in multiple breast cancer patients as well as prostate and colorectal cancer patients (Lolas Hamameh S et al. Int J Cancer. 2017 Aug 15;141(4):750-756; Pilie PG et al. Cancer. 2017 Oct 15;123(20):3925-3932; Decker B et al. J Med Genet. 2017 Nov;54(11):732-741; Wang YA et al. BMC Cancer. 2018 Mar 22;18(1):315; Xu Y et al. Front Oncol, 2020 Sep;10:1603; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Invitae	RCV000233154	SCV000282894	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu762Valfs*2) 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 present in population databases (rs587781658, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8789452, 8845835, 9463314, 21792198, 27484032). ClinVar contains an entry for this variant (Variation ID: 141325). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000233154	SCV000485904	likely pathogenic	Ataxia-telangiectasia syndrome	2016-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000480339	SCV000567457	pathogenic	not provided	2023-06-13	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 8789452, 15928302, 26045716, 9259193, 27484032, 26786923, 8845835, 29922827, 9463314, 21792198, 20852892, 1551665, 14695997, 21459046, 28779002, 28152038, 27304073, 29566657, 28486781, 28657667, 32853339, 30549301, 35022142, 33804961, 33471991, 32984025, 24789685, 35261632, 34771661, 35741767, 34196900, 34887416, 26896183)
Genetic Services Laboratory, University of Chicago	RCV000233154	SCV000593514	pathogenic	Ataxia-telangiectasia syndrome	2016-12-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129801	SCV000682047	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 15 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 in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8789452, 8845835, 9463314, 21792198). This variant has also been reported in individuals affected with breast cancer, prostate cancer, or familial colorectal cancer type X (PMID: 28486781, 28657667, 28779002, 29566657, 32984025, 33471991). This variant has been identified in 2/251234 chromosomes 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	RCV000233154	SCV001623380	pathogenic	Ataxia-telangiectasia syndrome	2021-04-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2284_2285delCT (p.Leu762ValfsX2) 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. The variant allele was found at a frequency of 8e-06 in 251234 control chromosomes. c.2284_2285delCT has been widely reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (example, Gilad_1996, Hacia_1998, Stankovic_1998, Jackson_2016). These data indicate that the variant is very likely to be associated with disease. Eight 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 (n=7)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003460902	SCV004206992	pathogenic	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing
GeneReviews	RCV000233154	SCV000328299	pathogenic	Ataxia-telangiectasia syndrome	2016-10-27	no assertion criteria provided	literature only
Natera, Inc.	RCV000233154	SCV001462062	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354163	SCV001548707	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu762ValfsX2 variant was identified in 2 of 4040 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer and severe combined immune deficiency and was not identified in 3994 control chromosomes from healthy individuals (Yu 2016, Thompson 2016). The variant was also identified in dbSNP (ID: rs587781658) as “With Pathogenic allele”. In addition, the variant was identified in the ClinVar database as pathogenic by Ambry Genetics, Invitae, GeneDx, Genetics Services Laboratory, University of Chicago and as likely pathogenic by Counsyl; and in the Clinvitae database as pathogenic by Invitae. The variant was further reported 4X in the LOVD 3.0 database. The variant was not identified in the following databases: COGR, Cosmic, MutDB, ATM-LOVD, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2284_2285del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 762 and leads to a premature stop codon at position 763. This alteration is then predicted to result in a truncated or absent protein and loss of function. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.