rs864622251

Variant names:

• chr11-108316030-G-A
• rs864622251
• NM_000051.4:c.6115G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108316030-G-A
• chr11-108316030-G-C
• chr11-108316030-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2039V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 9.22
• Publications: 22 publications found

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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 219787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6115G>A	p.Glu2039Lys	missense_variant	Exon 42 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6115G>A	p.Glu2039Lys	missense_variant	Exon 42 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251392 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000426 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3 Uncertain:1

Mar 14, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 identified 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; Boujemaa M et al. Front Genet, 2024 Jan;15:1327894). 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 other ATM variants 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. -

Jan 26, 2022

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Functional studies have reported that this variant does not affect protein expression but causes a reduction in kinase activity (PMID: 19431188). In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been reported in additional individuals affected with breast cancer (PMID: 19781682, 28975465, 30303537, 35893033, 38017116) as well as in individuals affected with prostate cancer (PMID: 35892882). 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: 26896183, 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. -

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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). -

Familial cancer of breast Pathogenic:3

-

Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 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: 22071889, 30549301, 27142713]. Functional studies indicate this variant impacts protein function [PMID: 19431188, 30549301]. -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Pathogenic:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). ClinVar contains an entry for this variant (Variation ID: 219787). 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) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188, 22071889). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 21, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 23532176, 30549301, 33471991, 28975465, 19431188, 30303537, 35892882, 32295079, 26896183, 35893033, 33280026, 39669589, 38017116, 38313678) -

ATM-related disorder Pathogenic:1

Jan 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		9.2
PrimateAI	Uncertain	0.74	T
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	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.88
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864622251; hg19: chr11-108186757; COSMIC: COSV53740536; COSMIC: COSV53740536;