11-108272782-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM5PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.3214G>T (p.Glu1072*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID:9443866, 26896183, 30579816). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008797 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16613125/MONDO:0700270/020

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ATM
NM_000051.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 3.28

Variant links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.3214G>T	p.Glu1072*	stop_gained	Exon 22 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.3214G>T	p.Glu1072*	stop_gained	Exon 22 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251360

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727100

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:3

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu1072*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9443866, 22585167). ClinVar contains an entry for this variant (Variation ID: 407699). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.3214G>T (p.Glu1072X) 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 4e-06 in 251360 control chromosomes. c.3214G>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Soukupova_2011, Mitui_2005, Jackson_2016). These data indicate that the variant is likely to be associated with disease. Six 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Sep 18, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Jan 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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); Identified in the heterozygous state in individuals with pancreatic cancer (Roberts et al., 2012; Hutchings et al., 2019); This variant is associated with the following publications: (PMID: 8808599, 22585167, 25525159, 9443866, 30579816, 21833744, 31285527, 16266405) -

Familial cancer of breast

Pathogenic:2

Jan 19, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Oct 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related cancer predisposition

Pathogenic:1

Nov 26, 2024

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.3214G>T (p.Glu1072*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 9443866, 26896183, 30579816). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008797 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) -

Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to

Pathogenic:1

Nov 13, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3214G>T (p.Glu1072*) variant in exon 22 of the ATM gene introduces a premature termination codon and is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been observed in at least two patients with ataxia telangiectasia for which the second allele is both known to be in trans, and is a pathogenic variant (PMID 21833744 and 16266405). This variant is has been observed only once in a heterozygous state in a large population database (gnomAD). Therefore, the c.3214G>T (p.Glu1072*) variant in the ATM gene is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Oct 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1072* pathogenic mutation (also known as c.3214G>T), located in coding exon 21 of the ATM gene, results from a G to T substitution at nucleotide position 3214. This changes the amino acid from a glutamic acid to a stop codon within coding exon 21. This mutation has been detected in conjunction with a second ATM alteration in numerous patients with Ataxia-Telangiectasia (A-T) (Wright J et al. Am. J. Hum. Genet., 1996 Oct;59:839-46; Telatar M et al. Am. J. Hum. Genet., 1998 Jan;62:86-97; Teraoka SN et al. Am J Hum Genet, 1999 Jun;64:1617-31; Mitui M et al. Ann. Hum. Genet., 2005 Nov;69:657-64; Soukupova J et al. Neuromolecular Med., 2011 Sep;13:204-11; Paucar M et al. Parkinsonism Relat Disord, 2019 05;62:253-255). This mutation has also been detected in patients with pancreatic and ovarian cancer (Roberts NJ et al. Cancer Discov, 2012 Jan;2:41-6; Harter P et al. PLoS One, 2017 Oct;12:e0186043; Hutchings D et al. Mod Pathol, 2019 12;32:1806-1813). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.94

Vest4

0.90, 0.91

GERP RS

2.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over