rs747855862

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_SupportingPM3_StrongPVS1_Strong

This summary comes from the ClinGen Evidence Repository: The ATM c.332-1G>A variant is predicted to create an NMD-escaping transcript resulting in a loss of part of the HEAT repeat domain (PVS1_strong). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID:10980530, PM3_strong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6264590/MONDO:0016419/020

Frequency

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

Consequence

ATM
NM_000051.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 9.15

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:

ATM (HGNC:):

ATM links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 9 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.332-1G>A		splice_acceptor_variant, intron_variant		ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.332-1G>A		splice_acceptor_variant, intron_variant			NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

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:

0.00000400

AC:

AN:

249988

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135310

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:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

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

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Nov 22, 2022	The ATM c.332-1G>A variant is predicted to create an NMD-escaping transcript resulting in a loss of part of the HEAT repeat domain (PVS1_strong). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PMID: 10980530, PM3_strong). This variant is a singleton in gnomAD v2.1.1 and therefore considered rare (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 09, 2024	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	This pathogenic variant is denoted ATM c.332-1G>A or IVS4-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 4 of the ATM gene. A splicing assay reportedly demonstrated that this variant, also defined as IVS6-1G>A using alternate numbering, results in the skipping of the adjacent exon (Laake 2000). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. ATM c.332-1G>A was observed in trans with another ATM variant in an individual with Ataxia-Telangiectasia (Laake 2000). Based on currently available evidence, we consider this variant to be likely pathogenic. -

Ataxia-telangiectasia syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2022

Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10980530). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Studies have shown that disruption of this splice site results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 10980530; Invitae). ClinVar contains an entry for this variant (Variation ID: 231535). This variant is also known as IVS6-1 G>A. This variant is present in population databases (rs747855862, gnomAD 0.005%). This sequence change affects an acceptor splice site in intron 4 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

The c.332-1G>A pathogenic intronic variant results from a G to A substitution one nucleotide upstream from coding exon 4 of the ATM gene. This alteration has been detected in an individual with ataxia-telangiectasia confirmed in trans with another ATM pathogenic mutation, and RNA analysis of this alteration showed skipping of exon 5 leading to an in-frame deletion of 165 base pairs or 55 amino acids (Laake K et al. Hum. Mutat. 2000 Sep; 16(3):232-46). Another study detected this alteration in 0/3030 patients with pancreatic cancer, 1/53105 controls from the ExAC population database, and 0/123136 controls from the gnomAD population database (Hu C et al. JAMA. 2018 06;319:2401-2409). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.93

Position offset: 1

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