NM_000051.4:c.3576G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM3

This summary comes from the ClinGen Evidence Repository: The c. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID:9887333, 21965147; Ambry internal data). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID:21965147, 26896183, 30819809). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000035 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1_Strong (RNA), PM3_Very Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA193897/MONDO:0700270/020

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:27

Conservation

PhyloP100: 8.97

Publications

32 publications found

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 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

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 6 ACMG points.

PVS1

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 rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.3576G>A	p.Lys1192Lys	splice_region_variant, synonymous_variant	Exon 24 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.3576G>A	p.Lys1192Lys	splice_region_variant, synonymous_variant	Exon 24 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151980

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251126

AF XY:

0.0000221

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461228

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726966

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111526

Other (OTH)

AF:

0.00

AC:

AN:

60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000762

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:8

Institute of Human Genetics, University Hospital of Duesseldorf

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 02, 2018

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 24, 2018

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATM c.3576G>A (p.Lys1192Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. An experimental study, Demuth_2011, supports these predictions by finding that this variant is associated with an in-frame exclusion of exon 26 from the mRNA. The variant allele was found at a frequency of 1.6e-05 in 246056 control chromosomes (gnomAD). The variant, c.3576G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Chessa_2009, Demuth_2011). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Mar 08, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 1192 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587776551, gnomAD 0.004%). This variant has been observed in individuals with ataxia-telangiectasia and early-onset breast and thyroid cancer (PMID: 8845835, 9887333, 17124347, 19691550, 22071889, 27599564). This variant is also known as 3403del174. ClinVar contains an entry for this variant (Variation ID: 3035). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 22071889). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 24, but is expected to preserve the integrity of the reading-frame (PMID: 9887333; internal data). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:8

Jul 13, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Located at the last nucleotide of exon 24 (also known as exon 26 in the literature) and demonstrated to result in abnormal splicing leading to skipping of exon 24 and/or exon 24-25 (Sandoval et al., 1999; Teraoka et a., 1999; Demuth et al., 2011; Jacquemin et al., 2012); Published functional studies demonstrate a damaging effect: reduced or absent protein expression and kinase activity (Sandoval et al., 1999; Teraoka et al., 1999; Demuth et al., 2011; Jacquemin et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer and other cancers (Prodosmo et al., 2016; Huang et al., 2018; Akcay et al., 2020; Asadollahi et al., 2020; Pastorino et al., 2020); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21965147, 10873394, 16941484, 17124347, 9463314, 21665257, 16189143, 11382771, 22927201, 27664052, 17910737, 22071889, 12552559, 10330348, 9450906, 9792409, 9443866, 22213089, 11606401, 15503472, 19691550, 8845835, 30819809, 30620386, 9887333, 29625052, 31741144, 32658311, 32325837, 32748564, 26896183, 33624863, 27599564) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM: PM3:Very Strong, PM2, PVS1:Moderate -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.3576G>A (p.Lys1192=) synonymous variant has been reported in the published literature in compound heterozygotes and homozygotes individuals with ataxia-telangiectasia (PMIDs: 35257272 (2022), 30819809 (2019), 27599564 (2016), 22213089 (2011)). Functional evidence indicates that this variant results in aberrant mRNA splicing and impacts protein function (PMIDs: 21965147 (2011), 22071889 (2011), 9887333 (1999), 9497252 (1998)). The frequency of this variant in the general population, 0.000016 (4/251126 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper ATM mRNA splicing. Based on the available information, this variant is classified as pathogenic. -

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

- -

Familial cancer of breast

Pathogenic:3

Mar 07, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 -

Jan 22, 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: 9887333]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8698354]. -

ATM-related cancer predisposition

Pathogenic:2

Nov 26, 2024

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c. 3576G>A (p.Lys1192=) variant is a synonymous (silent) variant in ATM. It is predicted to cause skipping of a biologically-relevant-exon, resulting in an in-frame deletion that is predicted to escape nonsense mediated decay. This prediction is confirmed by RNA analysis (PMID: 9887333, 21965147; Ambry internal data). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 21965147, 26896183, 30819809). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000035 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1_Strong (RNA), PM3_Very Strong) -

Jan 04, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:2

Jun 21, 2024

Institute of Human Genetics, Heidelberg University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant alters the conserved c.G at the last nucleotide position of exon 24 of the ATM gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies have shown that this variant causes in-frame skipping of exon 24 (hence, known as 3403del174 and p.Ser1135_Lys1192del58 in the literature) or out-of-frame skipping of exons 24 and 25 (PMID: 9887333, 21965147). This variant has been shown to significantly affect protein stability and kinase activity (PMID: 9887333, 21965147, 22071889). This variant has been reported in multiple individuals and families affected with ataxia-telangiectasia and is recurrent in Turkish and Italian populations (PMID: 9792409, 9887333, 16941484, 17124347, 19691550, 22071889, 30819809, 31741144, 34107524, 35257272). This variant has also been reported in at least two individuals affected with breast cancer (PMID: 27599564, 29665859). This variant has been identified in 4/251126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Nov 01, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3576G>A pathogenic mutation (also known as p.K1192K) is located in coding exon 23 of the ATM gene. This pathogenic mutation results from a G to A substitution at nucleotide position 3576. This nucleotide substitution does not change the lysine at codon 1192. However, this change occurs in the last base pair of coding exon 23 which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported frequently in individuals with a clinical diagnosis of ataxia telangiectasia, and has been observed in the homozygous state in individuals with severe disease (Chessa L et al. Ann. Hum. Genet. 2009 Sep;73(Pt 5):532-9; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72(Pt 1):10-8; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This alteration has been demonstrated to cause abnormal splicing, resulting in skipping of exon 23 (referred to as exon 26 in the literature) (Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Furthermore, several studies have shown that this alteration results in decreased/absent ATM protein expression and very low ATM kinase activity (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, c.3576G>A is classified as a pathogenic mutation. -

Breast and/or ovarian cancer

Pathogenic:1

Jun 15, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of pancreas

Pathogenic:1

Karaiskakio Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

9.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

Splicevardb

3.0

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.95

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over