rs139770721

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.6095G>A(p.Arg2032Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: 9.47

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 12 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-108315911-G-A is Pathogenic according to our data. Variant chr11-108315911-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108315911-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.6095G>A	p.Arg2032Lys	missense_variant, splice_region_variant	Exon 41 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.6095G>A	p.Arg2032Lys	missense_variant, splice_region_variant	Exon 41 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152086

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251394

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135878

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458372

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725756

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000202

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:7

Nov 15, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM3,PP3 -

Jan 30, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.6095G>A (p.R2032K) variant in the ATM gene has been reported in multiple Ataxia-telangiectasia (AT) patients with significantly higher prevalence [PMID: 10980530, 15390180,16266405] than that observed as extremely low in general population according to gnomad database. This variant, in trans with other deleterious variants, has been reported in AT patients [PMID: 27159176, 25614872]. Functional studies showed that this mutant causes abnormal splicing and loss of expression of ATM proteins [PMID: 9887333, 10330348]. Multiple in silico predictions suggest this arginine to lysine is deleterious, while the c.6095G>A change might affect the splicing of messenger RNA as the last nucleotide on exon 41. Based upon above evidences, this c.6095G>A (p.R2032K) variant in the ATM gene is classified as pathogenic. -

Mar 29, 2024

Baylor Genetics

Significance: 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: 16266405]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 9887333, 10330348]. -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3_MOD, PM3_VSTR -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:6

Apr 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alters the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and published functional studies and splice predictors support a deleterious effect (Telatar et al., 1998); Observed in the heterozygous state in individuals with ATM-related and other cancers (Thorstenson et al., 2003; Roberts et al., 2012; Huang et al., 2015; Yurgelun et al., 2015; Podralska et al., 2018; Waszak et al., 2018; Schubert et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15390180, 32875559, 28888541, 31921190, 20153123, 22585167, 12810666, 10817650, 10980530, 25980754, 26506520, 27878467, 29678143, 9443866, 10330348, 16266405, 27159176, 25614872, 9887333, 29753700, 30426508, 30772474, 23532176, 29625052, 31447099, 33077847, 34522244, 29922827, 34308104) -

Jan 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.6095G>A; p.Arg2032Lys variant (rs139770721) is recurrently reported in the medical literature in the compound heterozygous or homozygous state in individuals affected with ataxia-telangiectasia and has been described as a founder mutation in the Polish population (Cavaciuti 2005, Laake 2000, Mitui 2005, Podralska 2014). This variant has also been reported in cohorts affected with pancreatic cancer (Roberts 2012), gastric cancer (Huang 2015, Li 2000), and breast cancer (Schubert 2019, Thorstenson 2003). This variant is also reported in ClinVar (Variation ID: 181974). This variant is found in the non-Finnish European population with an allele frequency of 0.006% (7/113718 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.436); however, computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing through loss of a nearby splice donor site, and mRNA analyses revealed skipping of exon 41 (also known as exon 43) in lymphocytes derived from an affected individual (Sandoval 1999). Loss of exon 41 is predicted to lead to a frameshift resulting in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Cavaciuti E et al. Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer. 2005 Jan. PMID: 15390180. Huang DS et al. Prevalence of deleterious ATM germline mutations in gastric cancer patients. Oncotarget. 2015 Dec 1. PMID: 26506520. Laake K et al. Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum Mutat. 2000 Sep. PMID: 10980530. Li A et al. Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet. 2000 May 29. PMID: 10817650. Mitui M et al. ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia. Ann Hum Genet. 2005 Nov. PMID: 16266405. Podralska MJ et al. Ten new ATM alterations in Polish patients with ataxia-telangiectasia. Mol Genet Genomic Med. 2014 Nov. PMID: 25614872. Roberts NJ et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer discovery. 2012 Jan. PMID: 22585167. Sandoval N et al. Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet. 1999 Jan. PMID: 9887333. Schubert S et al. The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. Int J Cancer. 2019 Jun 1. PMID: 30426508. Thorstenson YR et al. Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 2003 Jun 15. PMID: 12810666. -

Feb 05, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.6095G>A (p.Arg2032Lys) variant has been reported in the published literature in individuals with ataxia-telangiectasia (PMID: 31921190 (2019), 30772474 (2019), 27159176 (2016), 25614872 (2014), 16266405 (2005), 10980530 (2000), 10330348 (1999), 9887333 (1999)), breast cancer (PMID: 30426508 (2018)), pancreatic cancer (PMID: 22585167 (2012)), and gastric cancer (PMID: 26506520 (2015)). Functional studies demonstrated that this variant disrupted mRNA splicing resulting in premature termination of the protein (PMID: 10330348 (1999), 9887333 (1999)). The frequency of this variant in the general population, 0.000062 (7/113718 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its 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 pathogenic. -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM3:Very Strong, PVS1, PM2 -

Ataxia-telangiectasia syndrome

Pathogenic:4

Dec 07, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2032 of the ATM protein (p.Arg2032Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs139770721, gnomAD 0.006%). This missense change has been observed in individuals with ataxia-telangiectasia, pancreatic cancer, or gastric cancer (PMID: 9887333, 10330348, 10980530, 16266405, 22585167, 25614872, 26506520, 27159176). ClinVar contains an entry for this variant (Variation ID: 181974). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 41 (also referred to as exon 43) , and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9887333; internal data). For these reasons, this variant has been classified as Pathogenic. -

Dec 23, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Jul 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 41 of the ATM gene and replaces arginine with lysine at codon 2032 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies using carrier-derived RNA have shown that this variant causes the skipping of exon 41 (also known as exon 43 in the literature), creating a premature translation stop signal (PMID: 9443866, 9887333, 10980530). The aberrant transcript is expected to result in an absent or non-functional protein product. Functional cytometric analysis of cells from individuals carrying this variant and affected with chronic lymphocytic leukemia showed decreased kinase activity (PMID: 36029002). This variant has been described as a recurrent mutation in the Polish population (PMID: 9443866, 16266405) and has been reported in many individuals affected with ataxia-telangiectasia (PMID: 9443866, 9887333, 10330348, 10817650, 10980530, 16266405, 25614872, 27159176) or adult-onset focal dystonia (PMID: 37445923). This variant has also been reported in individuals affected breast cancer, prostate cancer, pancreatic cancer or gastric cancer (PMID: 22585167, 26506520, 29678143, 31012270, 34377931). In a large international case-control study, this variant was reported in 9/60466 breast cancer cases and 4/53461 controls (OR=1.989, 95%CI 0.613 to 6.461, p-value=0.279; PMID: 33471991). This variant has been identified in 7/251394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Sep 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6095G>A pathogenic mutation (also known as p.R2032K), located in coding exon 40 of the ATM gene, results from a G to A substitution at nucleotide position 6095. The amino acid change results in arginine to lysine at codon 2032, an amino acid with highly similar properties. This alteration has been described as a founder mutation in the Polish population and has been detected in conjunction with a second mutation in numerous probands with ataxia-telangiectasia (A-T) (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64. Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Beier R et al. Bone Marrow Transplant. 2016 09;51:1271-4). This mutation has also been reported in high-risk breast cancer cohorts (Schubert S et al. Int. J. Cancer 2018 Nov; Podralska M et al. Mol Genet Genomic Med 2014 Nov;2(6):504-11). This change occurs in the highly-conserved last base pair of coding exon 40, which makes it likely to have some effect on normal mRNA splicing. RT-PCR analysis performed on RNA isolated from an A-T individual with this alteration was reported to result in exon skipping (Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have shown the same abnormal splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Carcinoma of pancreas

Pathogenic:1

Mar 04, 2021

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ATM-related disorder

Pathogenic:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.6095G>A variant is predicted to result in the amino acid substitution p.Arg2032Lys. Of note, this variant occurs at the last nucleotide of the exon and is predicted to significantly weaken the donor splice site (Alamut Visual Plus v1.6.1) and exon skipping was observed in analyses from patient lymphocytes (Sandoval et al 1999. PubMed ID: 9887333). This variant has been observed in the compound heterozygous or homozygous state in individuals with ataxia telangiectasia (Sandoval. 1999. PubMed ID: 9887333; Teraoka et al. 1999. PubMed ID: 10330348; Mitui et al. 2005. PubMed ID: 16266405). The c.6095G>A variant has also been reported in the heterozygous state in several individuals with pancreatic cancer, gastric cancer, prostate cancer, and breast cancer (Roberts et al. 2012. PubMed ID: 22585167; Huang et al. 2015. PubMed ID: 26506520; Table 1, Wokołorczyk D et al 2020. PubMed ID: 32875559; Schubert S et al 2019. PubMed ID: 30426508). This variant was reported as a germline variant in a patient with chronic lymphocytic leukemia (Table S2. Petrackova et al. 2022. PubMed ID: 36029002). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is reported as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/181974/). This variant is interpreted as pathogenic. -

Adenocarcinoma

Pathogenic:1

Oct 05, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain

0.51

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;.

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.99

D;D

Vest4

0.68

MVP

0.98

MPC

0.42

ClinPred

0.77

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.54

Position offset: 0

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