11-108271147-G-T

Variant names:

• chr11-108271147-G-T
• rs587781558
• NM_000051.4:c.2921+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):​c.2921+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,346 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (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:12
• Conservation: PhyloP100: 7.71
• Publications: 21 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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 11-108271147-G-T is Pathogenic according to our data. Variant chr11-108271147-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.2921+1G>T		splice_donor intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.2921+1G>T		splice_donor intron	N/A	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.2921+1G>T		splice_donor intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.2921+1G>T		splice_donor intron	N/A	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.2921+1G>T		splice_donor intron	N/A	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151712 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461634 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111870

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151712 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41260

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:4

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2921+1G>T variant is located in the canonical donor splice site of intron 19, and it is predicted to cause the skipping of exon 19 and disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). There is a pathogenic variant (c.2921+1G>A) in the same position, and the in silico splicing algorithm SPiCE predicts the same impact for both variants (PS1_Supporting). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS1_Supporting (PMID: 33280026).

Nov 27, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Aug 08, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to T nucleotide substitution at the +1 position of intron 19 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. A different variant affecting the same nucleotide position (c.2921+1G>A) is considered to be disease-causing (ClinVar variation ID: 141182), suggesting that the reference nucleotide at this position is important for normal RNA splicing. This variant has been reported in individuals affected with breast cancer (PMID: 34204722) or colorectal cancer (PMID: 29478780). This variant has not been identified 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 Likely Pathogenic.

Jun 11, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2921+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 18 of the ATM gene. Another alteration at this same nucleotide position has been reported in a homozygous state in one patient with a clinical diagnosis of ataxia-telangiectasia and in a compound heterozygous state in three patients with clinical diagnoses of ataxia-telangiectasia (Gilad S et al. Hum. Mol. Genet. 1996 Apr;5:433-9; Castellví-Bel S et al. Hum. Mutat. 1999;14:156-62; García-Pérez MA et al. Clin. Exp. Immunol. 2001 Mar;123:472-80; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). In addition to the clinical data presented in the literature, RNA studies detected abnormal splicing in individuals with the c.2921+1G>T alteration (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.

Ataxia-telangiectasia syndrome Pathogenic:3

Nov 04, 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 19 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ataxia-telangiectasia, colorectal cancer (PMID: 8845835, 11298136, 29478780). ClinVar contains an entry for this variant (Variation ID: 142057). Studies have shown that disruption of this splice site results in skipping of exon 19, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11298136; internal data). For these reasons, this variant has been classified as Pathogenic.

Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Pathogenic:2

Jan 22, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered 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.

Oct 09, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

Feb 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jan 24, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29478780, 28152038)

Malignant tumor of breast Pathogenic:1

Aug 01, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.2921+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251304 control chromosomes. c.2921+1G>T has been reported in the literature in two individuals affected with Colorectal cancer and early onset Rhabdomyosarcoma, respectively (examples: AlDubayan_2018, Kim_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different change c.2921+1G>A at this location has been reported in individuals with breast cancer and ovarian cancer and with ataxia-telangiectasia (Pathogenic at Labcorp with Ataxia Telangiectasia, 17 Pathogenic/clinical testing in ClinVar). The following publications have been ascertained in the context of this evaluation (PMID: 29478780, 34308104). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.7
GERP RS		5.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: -1

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

Other links and lift over

dbSNP: rs587781558; hg19: chr11-108141874; COSMIC: COSV53748775;