rs587781658

Positions:

• chr11-108257511-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):​c.2284_2285delCT​(p.Leu762fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.69

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108257511-ACT-A is Pathogenic according to our data. Variant chr11-108257511-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.2284_2285delCT	p.Leu762fs	frameshift_variant	15/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2284_2285delCT	p.Leu762fs	frameshift_variant	15/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251234 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461354 Hom.: 0 AF XY: 0.0000165 AC XY: 12 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Oct 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2023

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) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781658; hg19: chr11-108128238;