11-108312424-G-T

Position:

chr11-108312424-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1PP3PP5_Very_Strong

The NM_000051.4(ATM):c.5932G>T(p.Glu1978Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,595,290 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ATM
NM_000051.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:28O:1

Conservation

PhyloP100: 8.65

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 17 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP3

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

PP5

Variant 11-108312424-G-T is Pathogenic according to our data. Variant chr11-108312424-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 127414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108312424-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5932G>T	p.Glu1978Ter	stop_gained	40/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.5932G>T	p.Glu1978Ter	stop_gained	40/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152150

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251182

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135808

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:

0.0000880

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1443140

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719082

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:

0.0000192

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2017	Variant summary: The ATM c.5932G>T (p.Glu1978X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.7327C>T [p.Arg2443X], c.7517_7520delGAGA [p.Arg2506fsX3], and c.7913G>A [p.Trp2638X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the control database ExAC and control cohorts reported in the literature at a frequency of 0.0000779 (10/128320 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant has been found in homozygosity and compound heterozygosity in numerous patients and families with ataxia-telangiectasia (Podralska_MGGM_2014; Birrell_HM_2005). Additionally, a large case-control study showed that the variant is enriched in heterozygous breast cancer patients in Eastern European populations (Odds Ratio = 5.6; 95% CI = 1.323.4; p = 0.01; Bogdanova_BCRT_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic for both ataxia-telangiectasia and hereditary cancer. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Glu1978*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs587779852, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 15880721, 16266405, 17124347, 18497957, 18807267, 19691550, 25614872). ClinVar contains an entry for this variant (Variation ID: 127414). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	case-control	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Apr 08, 2022	Data included in classification: Truncating nonsense variant with frameshift (https://doi.org/10.1007/s10549-008-0189-9) (PVS1_vstr) Bogdanova et al 2008 (https://doi.org/10.1007/s10549-008-0189-9) Mantel–Haenszel Odds Ratio (OR): 5.6, 95% CI: 1.3–21.4, P = 0.01 - p ≤0.05 and OR is above 2 (PS4_str) Termination at a codon prior to p.Arg3047 (PM5_sup) Identified in 8/32 alleles in probands with ataxia telangiectasia (https://doi.org/10.1002/humu.9341) Observations in multiple ataxia telangiectasia cases (PMID: 15880721, 16266405, 17124347, 18807267, 19691550, 25614872, 18497957) (PM3_vstr) Data not included in classification: Multiple classification as pathogenic in ClinVar Allele frequency in Non-Finnish Europeans (NFE), gnomAD v2.1 Jan 2019: 5/102582 (0.005%). Variant frequency is at a frequency of ≥0.001%. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000127414 / PMID: 9443866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 11, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Familial cancer of breast

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2024	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3_MOD, PM3_VSTR -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 20, 2022	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PM3 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 26, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 23, 2022	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2022	Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Telatar 1998, Teraoka 1999, Mitui 2005, Mort 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Soukupova 2008, Huang 2015, Hu 2016, Pritchard 2016, Yang 2016, Decker 2017, Brand 2018, Isaacsson Velho 2018, Penkert 2018); Case control studies suggest this variant is associated with breast cancer (Bogdanova 2009, Zhang 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26483394, 26681312, 21514219, 24451234, 10817650, 16266405, 9872980, 8808599, 10330348, 19781682, 9443866, 18807267, 18497957, 26380989, 26506520, 25525159, 27112364, 10980530, 27449771, 27433846, 28779002, 29368341, 29625052, 30322717, 30113427, 30549301, 30067863, 30086788, 34426522, 32295079, 15880721, 33077847, 31589614, 33436325, 33726816, 32441320, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2021	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5932G>T, in exon 40 that results in the creation of a premature stop codon at amino acid position 1978, p.Glu1978. This variant is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. The p.Glu1978 change has been described in the gnomAD database with a frequency of 0.009% in the European sub-population (dbSNP rs587779852) and is a prevalent ATM variant in the Eastern European population (PMIDs: 15880721, 16266405, 18807267). This sequence change has been described in several individuals with ataxia-telangiectasia and breast cancer (PMIDs: 26380989, 30549301, 15880721, 16266405, 25614872, 17124347, 19691550, 18807267, 28779002, 30086788). The p.Glu1978* change has also been observed in individuals with pancreatic cancer, ovarian cancer, gastric cancer, and prostate cancer (PMIDs: 30067863, 27449771, 30322717, 26506520, 29368341). Functional studies have demonstrated skipping of exon 40 in the presence of this sequence change (PMIDs: 9443866, 10330348, 24451234). These collective evidences indicate that this is a pathogenic sequence change. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ATM: PVS1, PM2, PS4:Moderate, PS3:Supporting -

Breast and/or ovarian cancer

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 11, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This variant changes 1 nucleotide in exon 40 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has shown significant association with breast cancer in meta-analyses of multiple case-control studies (OR: 5.6, 95% CI: 1.3-21.4, p=0.01; PMID: 18807267) (OR: 4.56, 95% CI: 1.35-15.42, p=0.015; PMID: 21514219). This variant is a common cause of autosomal recessive ataxia-telangiectasia in Eastern Europe (PMID: 10330348, 15880721, 16266405). This variant has been identified in 11/251182 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2024	The p.E1978* mutation (also known as c.5932G>T), located in coding exon 39 of the ATM gene, results from a G to T substitution at nucleotide position 5932. This changes the amino acid from a glutamate to a stop codon within exon 40. This alteration has been reported in multiple individuals with ataxia-telangiectasia from various ethnic backgrounds and is likely a Russian founder mutation (Li A et al. Am. J. Med. Genet. 2000 May;92(3):170-7; Birrell GW et al. Hum. Mutat. 2005 Jun;25(6):593; 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(6):504-11). In addition, p.E1978* has been described as a breast cancer susceptibility allele of Eastern European origin (Bogdanova N et al. Breast Cancer Res. Treat. 2009 Nov;118(1):207-11). It was also seen in a patient with prostate cancer with a Gleason score of 9 (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53) and in cohorts of pancreatic cancer patients (Chaffee KG et al. Genet Med. 2018 01;20:119-127; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). This mutation was shown to cause skipping of coding exon 39 (reported as exon 42), as well as a premature truncation in a subset of ATM transcripts (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by aberrant splicing, premature protein truncation, or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 10, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 08-07-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Dec 19, 2019

This c.5932G>T (p.Glu1978Ter) variant in exon 41 of the ATM gene creates a premature translational stop signal and is predicted to result in loss of function through nonsense-mediated mRNA decay or by producing a truncated protein. This variant is present in population databases (rs587779852, gnomAD 0.004379%). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 15880721, 16266405, 17124347, 18497957, 19691550, 25614872) and breast cancer (PMID: 18807267). It has been found to be a prevalent ATM mutation in Eastern Europe (PMID: 15880721, 16266405, 18807267). Experimental studies indicate that this nonsense change leads to out-of-frame skipping of exon 41 (PMID: 10330348, 24451234). Therefore, this variant is classified as pathogenic. -

ATM-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2024

The ATM c.5932G>T variant is predicted to result in premature protein termination (p.Glu1978*). This variant has previously been reported by several studies in individuals with ataxia telangiectasia (Telatar et al 1998. PubMed ID: 9443866; Birrell et al. 2005. PubMed ID: 15880721; Mitui et al. 2005. PubMed ID: 16266405). This variant is also associated with breast cancer susceptibility (Bogdanova et al. 2009. PubMed ID: 18807267). This variant is particularly prevalent in families with a history of ataxia telangiectasia and who are of Eastern European decent (specifically Polish and Russian) (Mitui et al. 2005. PubMed ID: 16266405; Birrell et al. 2005. PubMed ID: 15880721). This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127414/?new_evidence=true). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;A;A

Vest4

0.94

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.61

Position offset: -13

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