11-108245000-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_ModeratePP3PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.875C>T variant in ATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 292 (p.Pro292Leu). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID:18634022, 30549301, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005% (1/19890 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). Experimental studies shows that this variant has impact on ATM kinase activity, protein levels and radiosensitivity was also found to be sensitive (RS<21%) when compared with wild type (PMID:18634022,19431188). The REVEL computational prediction analysis tool predicted a score of 0.752, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_strong, PS3_Moderate, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA6264689/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 7.33

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 Likely_pathogenic. Variant got 7 ACMG points.

PS3

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

PM3

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

PP3

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.875C>T	p.Pro292Leu	missense_variant	Exon 7 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.875C>T	p.Pro292Leu	missense_variant	Exon 7 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000806

AC:

AN:

248178

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134648

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1458632

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725798

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.875C>T (p.Pro292Leu) variant has been reported in the published literature in individuals with ataxia telangiectasia (PMID: 9463314 (1998), 10873394 (2000), 18634022 (2009), 21792198 (2011), 23264026 (2013), 26896183 (2016), 30549301 (2019)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 18634022 (2009), 19431188 (2009), 32694154 (2020)). The frequency of this variant in the general population, 0.000011 (3/279556 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Jun 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced ATM protein levels, reduced or absent kinase activity, and higher levels of radiosensitivity after exposure to ionizing radiation (PMID: 9463314, 10873394, 19431188, 18634022, 21792198); Observed in individuals with ATM-related cancers in published literature (PMID: 32694154, 31948886, 32957588); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25040471, 25482724, 36113475, 22529920, 12673797, 15279807, 12072877, 12552559, 15928302, 19431188, 21792198, 28359806, 9463314, 29922827, 30549301, 31948886, 10873394, 34404389, 32957588, 32694154, 26896183, 18634022, 23264026) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome

Pathogenic:4

Feb 04, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2024

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.875C>T (p.Pro292Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248178 control chromosomes. c.875C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (eg: Mitui_2009, Schon_2019, Reiman_2011, Jackson_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence has shown the variant leads to reduced or absent ATM kinase activity (Barone_2009, Mitui_2009). The following publications have been ascertained in the context of this evaluation (PMID: 18634022, 30549301, 21792198, 26896183, 19431188). ClinVar contains an entry for this variant (Variation ID: 229794). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 292 of the ATM protein (p.Pro292Leu). This variant is present in population databases (rs747727055, gnomAD 0.005%). This missense change has been observed in individuals with severe combined immunodeficiency and A-T and a milder phenotype of ataxia telangiectasia (A-T) (PMID: 10873394, 18634022, 19431188, 23264026, 30549301). This variant is also known as 1260C>T. ClinVar contains an entry for this variant (Variation ID: 229794). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 18634022, 19431188). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast

Pathogenic:3

Jan 11, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 12552559, 21792198, 23264026]. Functional studies indicate this variant impacts protein function [PMID: 18634022, 19431188, 21792198]. -

Mar 15, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.875C>T variant in ATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 292 (p.Pro292Leu). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 18634022, 30549301, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005% (1/19890 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). Experimental studies shows that this variant has impact on ATM kinase activity, protein levels and radiosensitivity was also found to be sensitive (RS<21%) when compared with wild type (PMID:18634022,19431188). The REVEL computational prediction analysis tool predicted a score of 0.752, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_strong, PS3_Moderate, PP3) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jan 07, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 292 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown instability and low-level expression of the mutant protein, and absent or reduced kinase activity, as well as high radiosensitivity after ionizing radiation exposure of cells carrying this variant (PMID: 18634022, 19431188). This variant has been reported in individuals affected with classic or mild form of ataxia-telangiectasia (PMID: 10873394, 18634022, 23264026, 30549301) and in individuals affected with breast cancer and/or ovarian cancer (PMID: 32957588, 38355628). This variant has been identified in 3/279556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

May 10, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P292L pathogenic mutation (also known as c.875C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 875. The proline at codon 292 is replaced by leucine, an amino acid with similar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in individuals with a clinical diagnosis of ataxia-telangiectasia (A-T), two of whom have had a typical phenotype and two of whom had a mild phenotype (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat., 2009 Jan;30:12-21; Schon K et al. Ann. Neurol., 2019 02;85:170-180). This alteration was also identified in individuals diagnosed with breast and/or ovarian cancer (Kansuttiviwat C et al. NPJ Genom Med, 2024 Feb;9:9). Functional analyses of p.P292L have shown reduced kinase activity, reduced protein levels, and increased radiosensitivity compared to wildtype ATM (Mitui M et al. Hum. Mutat., 2009 Jan;30:12-21; Barone G et al. Hum. Mutat., 2009 Aug;30:1222-30). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast carcinoma

Pathogenic:1

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;.

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.022

MutationAssessor

Uncertain

2.5

.;M;M

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.7

D;D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.91, 0.81

MutPred

0.80

Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);

MVP

0.96

MPC

0.59

ClinPred

1.0

GERP RS

5.1

Varity_R

0.50

gMVP

0.73

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