11-108316030-G-A

Position:

chr11-108316030-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.6115G>A(p.Glu2039Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,846 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: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 9.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 11-108316030-G-A is Pathogenic according to our data. Variant chr11-108316030-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219787.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.6115G>A	p.Glu2039Lys	missense_variant	42/63	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.6115G>A	p.Glu2039Lys	missense_variant	42/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251392

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

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:

0.00000274

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727224

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2023	This missense variant replaces glutamic acid with lysine at codon 2039 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 reported that this variant does not affect protein expression but causes a reduction in kinase activity. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 0/53461 controls (PMID: 33471991). This variant has been reported in additional individuals affected with breast cancer (PMID: 19781682, 28975465, 30303537, 35893033. This variant has also been reported in an individual affected with variant ataxia-telangiectasia with a co-occurring pathogenic variant, c.8609_8610delAT (p.Asp2870GlufsTer10), in unknown phase (PMID: 30549301). This variant was identified in a second individual affected with ataxia-telangiectasia with a co-occurring variant of uncertain significance, c.6491A4C (p.Glu2164Ala), in unknown phase (PMID: 22071889). This variant has been identified in 1/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.6115G>A (p.Glu2039Lys) variant appears only once in the gnomAD v2.1.1 non-cancer dataset (0.0004% frequency), 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). Functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line and proper controls showed that the protein was stable but but retained relatively little kinase activity (no functional criterion met; PMID: 19431188). The variant was found in one ataxia telangiectasia proband with another missense variant (PS4_Supporting; PMID: 22071889). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PP3 + PS4_Supporting (PMID: 33280026). -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2024	The p.E2039K variant (also known as c.6115G>A), located in coding exon 41 of the ATM gene, results from a G to A substitution at nucleotide position 6115. The glutamic acid at codon 2039 is replaced by lysine, an amino acid with similar properties. This variant has been detected in multiple individuals diagnosed with breast cancer (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46; Siraj AK et al. Hum Genet, 2017 11;136:1431-1444; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439; BenAyed-Guerfali D et al. Genes (Basel), 2022 Jul;13:; Bu R et al. Sci Rep, 2023 Nov;13:20924). Additionally, this variant has been identified in individuals diagnosed with prostate cancer (Mondschein R et al. Cancers (Basel), 2022 Jul;14:). This variant has been identified in the homozygous state and likely in trans with another ATM variant in individuals diagnosed with ataxia telangiectasia (Jacquemin V et al. Eur J Hum Genet, 2012 Mar;20:305-12; Schon K et al. Ann Neurol, 2019 02;85:170-180). Additional investigation has demonstrated stable, normally-localized ATM protein, but reduced kinase activity associated with p.E2039K compared to wild type (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30. Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar; 20(3):305-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 29, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22071889, 30549301, 27142713]. Functional studies indicate this variant impacts protein function [PMID: 19431188, 30549301]. -
Pathogenic, criteria provided, single submitter	clinical testing	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 15, 2023	- -

Ataxia-telangiectasia syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2039 of the ATM protein (p.Glu2039Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with ataxia-telangiectasia and/or breast cancer (PMID: 19781682, 22071889, 26896183, 30303537, 30549301; Invitae). ClinVar contains an entry for this variant (Variation ID: 219787). 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 tolerated. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188, 22071889). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

ATM-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2024

The ATM c.6115G>A variant is predicted to result in the amino acid substitution p.Glu2039Lys. This variant has been observed in multiple individuals with breast cancer (Table S2 - Tavtigian et al. 2009. PubMed ID: 19781682; Table S4 - Siraj et al. 2017. PubMed ID: 28975465). Additionally, this variant has been reported with another variant in the compound heterozygous state in an individual with ataxia-telangiectasia (Jacquemin et al. 2012. PubMed ID: 22071889). Functional studies demonstrated reduced kinase activity (Barone et al. 2009. PubMed ID: 19431188) and defective response to ionizing radiation (Jacquemin et al. 2012. PubMed ID: 22071889). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations of pathogenicity of uncertain and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/219787/). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2023

Published functional studies demonstrate a damaging effect: reduced kinase activity compared to wild type (PMID: 19431188, 22071889); Observed with a second ATM variant in patients with clinical features of ataxia-telangiectasia but it is not known whether the variants occurred on the same (in cis) or opposite (in trans) alleles (PMID: 22071889, 30549301); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22071889, 19781682, 30549301, 23532176, 33471991, 28975465, 19431188, 30303537, 35892882, 32295079, 33280026, 35893033, 26896183) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.81

Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);

MVP

0.97

MPC

0.24

ClinPred

0.92

GERP RS

5.2

Varity_R

0.23

gMVP

0.88

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