Variant rs786201675 details in Genebe, Genetics Data Aggregator

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]

ATM links:

ATM (HGNC:):

ATM links:

ACMG classification

Classification made for transcript

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 11-108282837-CTTTTA-C is Pathogenic according to our data. Variant chr11-108282837-CTTTTA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 184764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108282837-CTTTTA-C is described in Lovd as [Pathogenic]. Variant chr11-108282837-CTTTTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.3712_3716delTTATT	p.Leu1238fs	frameshift_variant	25/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.3712_3716delTTATT	p.Leu1238fs	frameshift_variant	25/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000795

AC:

AN:

1383008

Hom.:

AF XY:

0.00000867

AC XY:

AN XY:

691890

show subpopulations

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:

0.0000105

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:4

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.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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 29, 2022	PVS1 PS3 PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2017	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 29, 2022	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. -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 22, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	Aug 07, 2021	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 09, 2024	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 variant 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 23, 2021

- -

ATM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs786201675

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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