ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2284_2285del (p.Leu762fs) (rs587781658)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129801 SCV000184612 pathogenic Hereditary cancer-predisposing syndrome 2019-02-01 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 positions 2284 and 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 (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; 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 a prostate cancer patient (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). 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 2020-10-15 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with ataxia-telangiectasia (PMID: 8789452, 8845835, 21792198, 9463314, 27484032). ClinVar contains an entry for this variant (Variation ID: 141325). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). 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 2019-01-07 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in ATM is denoted c.2284_2285delCT at the cDNA level and p.Leu762ValfsX2 (L762VfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CACT[delCT]GTTT. The deletion causes a frameshift, which changes a Leucine to a Valine at codon 762, and creates a premature stop codon at position 2 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. Also published as ATM c.2284delCT and c.2282_2283del using alternate nomenclature, this variant has been reported in the homozygous or compound heterozygous state in individuals with a clinical diagnosis of Ataxia-Telangiectasia and an infant with severe primary immunodeficiency (Gilad 1996, Stankovic 1998, Exley 2011, Reiman 2011, Yu 2016). It has also been observed in the single heterozygous state in at least one individual with breast or ovarian cancer as well as in a child with acute lymphoblastic leukemia (ALL) (Liberzon 2004, Thompson 2016). We consider this variant to be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000233154 SCV000593514 pathogenic Ataxia-telangiectasia syndrome 2016-12-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129801 SCV000682047 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
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.
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.

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