11-108299886-G-C

Variant names:

• chr11-108299886-G-C
• rs1131691159
• NM_000051.4:c.5177+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_Supporting PVS1 PM2_Supporting

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

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: 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	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	c.5177+1G>C		splice_donor_variant, intron_variant	Intron 34 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460598 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726676

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

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	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs1131691159; hg19: chr11-108170613;