11-108299886-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM3_SupportingPM2_SupportingPVS1

This summary comes from the ClinGen Evidence Repository: The c.5177+1G>C variant in ATM occurs within the canonical splice donor site of intron 34. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID:26896183). This variant is absent from gnomAD v2.1.1. 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, PM3_Supporting, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA382541268/MONDO:0700270/020

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 8.35

Publications

3 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 10 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 rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.5177+1G>C		splice_donor_variant, intron_variant	Intron 34 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.5177+1G>C		splice_donor_variant, intron_variant	Intron 34 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460598

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111096

Other (OTH)

AF:

0.00

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 07, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5177+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 33 of the ATM gene. This nucleotide position is highly conserved in available vertebrate species. 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). 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. As such, this alteration is classified as likely pathogenic.

Jan 29, 2024

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 C nucleotide substitution at the +1 position of intron 34 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported for this variant, it is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported with a co-occurring intronic variant of uncertain significance in an individual affected with ataxia-telangiectasia (PMID: 26896183). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position, c.5177+1G>A, has been identified in an individual affected with bilateral breast cancer and family history of pancreatic and breast cancer (PMID: 18497957). An RNA study using cells from this heterozygous individual has shown that c.5177+1G>A variant results in exon 34 skipping (referred to as exon 36 in the article based on the U33841 transcript) and premature protein truncation, with almost no expression of normal transcripts from the mutant allele (PMID: 18497957). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

Ataxia-telangiectasia syndrome

Pathogenic:1

Nov 11, 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 34 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 individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 26896183, 29522266). ClinVar contains an entry for this variant (Variation ID: 857860). Studies have shown that disruption of this splice site results in skipping of exon 34 (also known as exon 36), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18497957). For these reasons, this variant has been classified as Pathogenic.

ATM-related cancer predisposition

Pathogenic:1

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.5177+1G>C variant in ATM occurs within the canonical splice donor site of intron 34. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 26896183). This variant is absent from gnomAD v2.1.1. 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, PM3_Supporting, PM2_Supporting)

ATM-related disorder

Pathogenic:1

Feb 05, 2021

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.5177+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage and hence is presumed to be rare. Soukupova et al. (2008), identified the c.5177+1G>A variant, a different nucleotide change at the same position, in a heterozygous state in a patient with bilateral breast cancer (ages: 42 and 44 years). Quantitative analysis of RNA samples from the patient indicated that the c.5177+G>A variant caused skipping of exon 36, when compared to controls. The skipping of exon 36 is predicted to cause premature termination at codon 1680 of the ATM protein. Based on the cumulative evidence, the c.5177+1G>C variant is classified as pathogenic for ATM-related disorders.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.0

.;.

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

8.3

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over