chr11-108335080-G-A

Position:

chr11-108335080-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.8122G>A(p.Asp2708Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.51

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:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a mutagenesis_site Decreased phosphorylation of target proteins. (size 0) in uniprot entity ATM_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 11-108335080-G-A is Pathogenic according to our data. Variant chr11-108335080-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142791.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 linkuse as main transcript	c.8122G>A	p.Asp2708Asn	missense_variant	55/63	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.8122G>A	p.Asp2708Asn	missense_variant	55/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251356

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 22, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2708 of the ATM protein (p.Asp2708Asn). This variant is present in population databases (rs587782719, gnomAD 0.003%). This missense change has been observed in individuals with ataxia telangiectasia (A-T) and/or cancer (PMID: 16941484, 21665257, 21792198, 22071889, 23454770, 23632773, 27913932, 29909963). ClinVar contains an entry for this variant (Variation ID: 142791). 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: 19431188, 22071889, 23454770, 23632773). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2022	The p.D2708N pathogenic mutation(also known as c.8122G>A), located in coding exon 54 of the ATM gene, results from a G to A substitution at nucleotide position 8122. The aspartic acid at codon 2708 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in conjunction with other pathogenic ATM mutations (phase confirmed in two cases) in several individuals with classic and variant ataxia telangiectasia (AT) (Micol R et al. J. Allergy Clin. Immunol. 2011;128(2):382-9; Claes K et al. Neuromolecular Med. 2013;15(3):447-57; Cavalieri S et al. Ann. Hum. Genet. 2008;72(Pt 1):10-8; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64). In two studies, this alteration was shown to demonstrate a significant reduction in ATM protein expression and kinase activity, as well as mislocalization of the protein (Jacquemin V et al. Eur. J. Hum. Genet. 2012;20(3):305-12; Barone G et al. Hum. Mutat. 2009;30(8):1222-30). In addition, a disease-causing mutation, p.D2708E, has been described at the same codon (Heinrich T et al. Eur. J. Pediatr. 2006; 165:250-7; Bisgin A et al. Biomed Res Int 2018 May;2018:9647253, Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9.e1; Jacquemin V et al. Eur. J. Hum. Genet. 2012; 20:305-12.). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 25, 2021	This missense variant replaces aspartic acid with asparagine at codon 2708 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant results in reduced ATM kinase activity (PMID: 19431188). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 16941484, 17124347, 17910737, 19431188, 21665257, 21792198, 22071889, 23632773, 25122203, 30338439). It has been reported that cells derived from some of these individuals display reduced kinase activity, protein expression and irradiation response and increased radiosensitivity (PMID: 22071889, 23632773). This variant has also been reported in individuals affected with breast cancer (PMID: 27913932, 28779002). This variant has been identified in 1/251356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.8122G>A (p.Asp2708Asn) variant appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the South-Asian subpopulation (PM2; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). It has been described in trans with the pathogenic ATM variant c.2250G>A in two ataxia-telangiectasia probands and together (unknown phase) with the pathogenic ATM variant c.3712_3716del in another ataxia-telangiectasia proband, which awards 2.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_Strong; PMID: 22071889, 16941484, 17124347). Studies in ataxia-telangiectasia patient carrier cells show no autophosphorilation in Serine 1981 and no (or trace) phosphorylation of 4 substrates upon irradiation, confirmed with two substrates by functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line. Intermediate irradiation sensitivity was found in a micronuclei assay (PS3_Moderate; PMID: 22071889, 23632773, 19431188). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules were applied as defined by the Spanish-ATM Variant Curation Panel: PM2 + PP3 + PM3_Strong + PS3_Moderate. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 (PMID: 33280026). -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 24, 2018	The ATM c.8122G>A; p.Asp2708Asn variant (rs587782719), is reported in the literature in a compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (A-T; Cavalieri 2006, Claes 2013, Jacquemin 2012, Magliozzi 2006, Prodosmo 2013, Reiman 2011) and one heterozygous individual with bilateral breast cancer and ovarian cancer (Tavera-Tapia 2017). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 142791), and is also largely absent from general population databases (not found in 1000 Genomes Project or Exome Variant Server, and one heterozygous individual in Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 2708 is highly conserved, and functional analyses of the variant protein show reduced kinase activity and increased radiosensitivity (Barone 2009, Claes 2013, Jacquemin 2012). Based on available information, this variant is considered to be likely pathogenic. Pathogenic variants in the ATM gene follow an autosomal recessive inheritance pattern and are associated with ataxia-telangiectasia (A-T; MIM: 208900), and an autosomal dominant inheritance pattern and are associated with an increased risk for breast cancer (MIM: 114480). References: Barone G et al. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat. 2009 Aug;30(8):1222-30. Cavalieri S et al. ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions. Hum Mutat. 2006 Oct;27(10):1061. Claes K et al. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives. Neuromolecular Med. 2013 Sep;15(3):447-57. Jacquemin V et al. Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet. 2012 Mar;20(3):305-12. Magliozzi M et al. DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations. Dis Markers. 2006;22(4):257-64. Prodosmo A et al. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes. J Clin Invest. 2013 Mar;123(3):1335-42. doi: 10.1172/JCI67289. Epub 2013 Feb 1. Reiman A et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br J Cancer. 2011 Aug 9;105(4):586-91. Tavera-Tapia A et al. Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene. Breast Cancer Res Treat. 2017 Feb;161(3):597-604. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2022	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: 19431188, 17124347, 22071889, 27913932, 17910737, 16941484, 23632773, 21792198, 29600275, 29909963, 27304073, 28779002, 23454770, 33436325, 29922827, 32980694, 33280026) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Familial cancer of breast

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 21665257, 17910737]. Functional studies indicate this variant impacts protein function [PMID: 22071889,19431188, 23632773]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 05, 2023	- -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 03, 2023

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Familial prostate cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 28, 2023

Variant summary: ATM c.8122G>A (p.Asp2708Asn) results in a conservative amino acid change located in the catalytic domain (IPR044107) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 (i.e., 1 heterozygote) in 251356 control chromosomes (gnomAD v2, exomes cohort). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8122G>A has been reported in the literature in multiple compound heterozygous individuals affected with classic- and variant Ataxia-Telangiectasia (A-T) (e.g., Thompson_2005, Cavalieri_2006, Reiman_2011, Jacquemin_2012, Prodosmo_2013, Claes_2013), and in heterozygous individuals affected with various tumor phenotypes, including prostate-, breast/ovarian-, and pancreatic cancer (e.g., Hata_2021, Karlsson_2021, Tavera-Tapia_2017, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased protein levels and kinase activity in an in vitro expression system (Barone_2009), and in patient derived cells (e.g. Reiman_2011, Jacquemin_2012, Prodosmo_2013, Claes_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 16941484, 23632773, 34755017, 22071889, 33436325, 23454770, 21792198, 27913932, 15928302, 29909963, 33471991). Multiple ClinVar submitters (evaluation after 2014) have cited the variant and all laboratories classified the variant as pathogenic (n = 4) or likely pathogenic (n = 8). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.044

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.82

Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);

MVP

0.98

MPC

0.55

ClinPred

0.98

GERP RS

5.7

Varity_R

0.52

gMVP

0.78

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