chr11-108245000-C-T

Position:

chr11-108245000-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PS3_ModeratePM3_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:15

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/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.875C>T	p.Pro292Leu	missense_variant	7/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.875C>T	p.Pro292Leu	missense_variant	7/63		NM_000051.4	ENSP00000501606	P1

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:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 18634022, 19431188). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 04, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 04, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2024	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. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial cancer of breast

Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Jan 25, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 11, 2024	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]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 11, 2020	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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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 (PMID: 32957588; Color internal data). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2024	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

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Breast carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

- -

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

MutationTaster

Benign

1.0

D;D

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