ENST00000526567.5:c.336G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The ENST00000526567.5(ATM):c.336G>A(p.Lys112Lys) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ATM
ENST00000526567.5 synonymous

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.24

Publications

7 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:

Y_RNA (HGNC:):

Y_RNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-108229328-G-A is Pathogenic according to our data. Variant chr11-108229328-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.331+5G>A		splice_region_variant, intron_variant	Intron 4 of 62	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.331+5G>A		splice_region_variant, intron_variant	Intron 4 of 62		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249372

AF XY:

0.00

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724808

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

85926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108578

Other (OTH)

AF:

0.00

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000341

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Oct 09, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and published functional studies demonstrate this variant causes skipping of exon 4, with reduced or absent ATM protein and kinase activity (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; van Os et al., 2017); Observed in the homozygous or compound heterozygous state in several individuals with ataxia-telangiectasia (Verhagen et al., 2009; Verhagen et al., 2012; Nakamura et al., 2012; Chen et al., 2013; van Os et al., 2017); Observed in the heterozygous state in individuals with prostate or ovarian cancer (Lilyquist et al., 2017; Darst et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Also reported as IVS6+5G>A using alternate intron nomenclature; This variant is associated with the following publications: (PMID: 23726790, 22006793, 19535770, 23566627, 22213089, 28126470, 19705055, 30549301, 29288088, 32853339, 29922827, 30850667, 37649078, 28888541) -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 18, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

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

- -

Ataxia-telangiectasia syndrome

Pathogenic:4

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.331+5G>A variant in ATM has been reported in at least 2 homozygous and 2 compound heterozygous individuals with ataxia-telangiectasia and segregated with disease in at least 1 affected family member (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793, Verhagen 2012 PMID: 22213089, Chen 2013 PMID: 23726790). It has also been reported in ClinVar (Variation ID 230851) but was absent from large population studies. This variant is located in the 5'/3' splice region. Computational tools do not provide strong support for a splicing impact, however, In vitro functional studies (including using patient tissue) support exon 6 (exon 5 on NM000051) skipping (introducing a frameshift) and an impact on ATM function (Verhagen 2009 PMID: 19535770, Nakamura 2012 PMID: 22006793). Loss of function of the ATM gene is an established disease mechanism in autosomal recessive ataxia telangiectasia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ataxia telangiectasia. ACMG/AMP Criteria applied: PM2_supporting, PVS1, PM3_Strong. -

Jun 29, 2016

Counsyl

Significance:Likely 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. -

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Splice variant predicted to produce a truncated protein by alternate splicing. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19535770). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.98). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 19535770, 22213089, 23726790). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 23726790). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230851 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 4 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs752135143, gnomAD 0.0009%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 19535770, 22006793, 22213089, 23726790). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 230851). 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: 19535770). 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 4, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast

Pathogenic:3

Aug 26, 2024

Department of Human Genetics, Hannover Medical School

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 09, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data, PMID: 17726045]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19535770, 22213089, 23726790]. -

Dec 19, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

May 05, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.331+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the ATM gene. In one study, this alteration was detected as homozygous in two related individuals diagnosed with ataxia-telangiectasia (A-T) and was correlated with decreased ATM protein levels and kinase activity (Verhagen MM et al, Neurology 2009 Aug; 73(6):430-7). This alteration has also been identified in several individuals with A-T as a compound heterozygous state (Morio T et al. Int. J. Hematol., 2009 Nov;90:455-462; Nakamura K et al. Hum. Mutat., 2012 Jan;33:198-208; Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71; Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 16, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a G>A nucleotide substitution at the +5 position of intron 4 of ATM. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. This variant has been reported to impact RNA splicing by external laboratories (ClinVar Accession: SCV000274529.8, SCV001219332.5, SCV004932145.1). This variant has been observed with a second pathogenic variant in trans in multiple individuals affected with ataxia-telangiectasia (PMID: 19535770, 19705055, 22006793, 22213089, 23726790). Patient derived samples showed decreased ATM protein levels and kinase activity (PMID: 19535770, 22213089). This variant has also been identified in 1/249372 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Feb 23, 2022

Fulgent Genetics, Fulgent Genetics

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

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.94

PhyloP100

7.2

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

Splicevardb

3.0

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -5

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