11-108252914-T-G

Variant names:

• chr11-108252914-T-G
• rs587782124
• NM_000051.4:c.1898+2T>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000051.4(ATM):​c.1898+2T>G variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000076 in 1,447,188 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 5.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010467779 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 11-108252914-T-G is Pathogenic according to our data. Variant chr11-108252914-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108252914-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1898+2T>G		splice_donor_variant, intron_variant	Intron 12 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1898+2T>G		splice_donor_variant, intron_variant	Intron 12 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249862 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135088

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1447188 Hom.: 0 Cov.: 28 AF XY: 0.00000694 AC XY: 5 AN XY: 720882

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: 0.0000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change in the canonical splice donor site of intron 12, c.1898+2T>G. This sequence change has been previously described in individuals with classic and atypical forms of ataxia-telangiectasia (PMID: 9463314, 23566627, 16266405) and also in one individual who later developed pancreatic adenocarcinoma (PMID: 24090759). It has also been reported in an individual with breast cancer (PMID: 10677309). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs587782124). This sequence change is predicted to affect normal splicing of the ATM gene and result in an abnormal protein. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). These colective evidences indicate that this sequence change is pathogenic. -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 13, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.1898+2T>G or IVS12+2T>G and consists of a T>G nucleotide substitution at the +2 position of intron 12 of the ATM gene. This variant destroys a canonical splice site and is predicted to cause abnormal gene splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also reported as ATM IVS14+2T>G, has been reported in the compound heterozygous state in individuals with Ataxia-telangiectasia, one of whom also developed pancreatic cancer (Stankovic 1998, Mitui 2005, Verhagen 2007, Cavalieri 2008, Davis 2013). Cell lines from two of these individuals demonstrated radiosensitivity and absence of ATM protein expression and kinase activity (Mitui 2005, Driessen 2013). Based on currently available evidence, we consider this variant to be pathogenic. -

Familial cancer of breast Pathogenic:3

Jan 16, 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 occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Jul 19, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1_STR,PM3,PM2_SUP -

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 24, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, also known as 'IVS14+2T>G', causes a T to G nucleotide substitution at the +2 position of intron 12 of the ATM gene. This variant has been reported in an individual affected with bilateral breast cancer diagnosed at the age of 35 and 43 (PMID: 10677309). This variant has also been reported with pathogenic variants in individuals affected with classic or variant ataxia-telangiectasia (PMID: 9463314, 16266405, 23566627, 24090759, 28126470). Several of these individuals were confirmed to have this variant in trans with a second pathogenic variant (PMID: 16266405, 23566627, 28126470). Cells derived from these individuals did not show kinase activity (PMID: 23566627, 28126470). This variant has been identified in 1/249862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1898+2T>G pathogenic mutation (also known as IVS14+2T>G) results from a T to G substitution two nucleotides after coding exon 11 in the ATM gene. This variant has previously been reported in multiple individuals with ataxia telangiectasia (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62(2):334-45; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Davis MY et al. J. Neurol. Sci. 2013 Dec;335(1-2):134-8; Driessen GJ. J Allergy Clin Immunol . 2013 May;131(5):1367-75.e9). It has also been identified in a Dutch breast cancer cohort, in one patient with breast cancer diagnosed at ages 35 and 43 (Broeks A et al. Am. J. Hum. Genet. 2000 Feb;66(2):494-500). Of note, this alteration is also designated as IVS14+2T>G in the published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ataxia-telangiectasia syndrome Pathogenic:1

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 12 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587782124, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 9463314, 10677309, 16266405, 16941484, 17985259, 23566627, 24090759). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS14+2T>G. ClinVar contains an entry for this variant (Variation ID: 141939). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (internal data). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782124; hg19: chr11-108123641;