rs200196781

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000051.4(ATM):​c.3993+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 11-108284474-G-A is Pathogenic according to our data. Variant chr11-108284474-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141447.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
ATMNM_000051.4 linkc.3993+1G>A splice_donor_variant, intron_variant Intron 26 of 62 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.3993+1G>A splice_donor_variant, intron_variant Intron 26 of 62 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250838
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135606
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:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461506
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727052
show subpopulations
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3
Jun 14, 2017
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 23, 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 26 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 40 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs200196781, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10980530, 12815592). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS28+1G>A. ClinVar contains an entry for this variant (Variation ID: 141447). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 26 (PMID: 10980530; internal data). For these reasons, this variant has been classified as Pathogenic. -

May 06, 2021
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Using RNA studies, this variant has been reported to result in an in-frame deletion of 40 amino acids (PMID: 10980530). However, specific data was not shown. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic in multiple submissions in ClinVar. It has also been reported as compound heterozygous in a patient with ataxia-telangiectasia (PMID: 12815592). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3
Oct 16, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 05, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15390180, 15039971, 29945567, 10980530, 26976419, 25186627, 32853339, 12815592) -

Hereditary cancer-predisposing syndrome Pathogenic:2
Nov 23, 2021
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 A nucleotide substitution at the +1 position of intron 26 of the ATM gene. A study using carrier-derived RNA has shown that this variant (also known as IVS28+1G>A in the literature) causes the deletion of 120 nucleotides from the 3' end of exon 26 (PMID: 10980530). The aberrant transcript is predicted to cause an in-frame deletion of 40 amino acids (p.Val1292_Gln1331del). This variant has been reported in trans with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 10980530, 12815592). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 26976419) and pancreatic cancer (PMID: 29945567). In a large international case-control study, this variant was reported in 4/60462 breast cancer cases and 5/53456 controls (OR=0.707, 95%CI 0.19 to 2.634, p-value=0.743; PMID: 33471991). This variant has been identified in 4/250838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jan 30, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3993+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 25 of the ATM gene. This alteration has been described in several ataxia-telangiectasia families (Laake K et al. Hum. Mutat. 2000; 16:232-46; Mitui M et al. Hum. Mutat. 2003; 22:43-50). This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration has also been identified in patients with pancreatic cancer (Young EL et al. BMC Cancer, 2018 Jun;18:697). 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 and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Of note, this alteration is also designated as IVS28+1G>A in published literature. 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. As such, this alteration is classified as pathogenic. -

Familial cancer of breast Pathogenic:2
Aug 26, 2022
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 16, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
Feb 04, 2025
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1;_Strong; PM3_Strong -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
GERP RS
5.4
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
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.49
Position offset: -43
DS_DL_spliceai
1.0
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.

Other links and lift over

dbSNP: rs200196781; hg19: chr11-108155201; COSMIC: COSV53767160; COSMIC: COSV53767160; API