rs17174393

chr11-108353881-G-Achr11-108353881-G-Cchr11-108353881-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.8786+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,608,514 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 Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 10.0

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 links:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-108353881-G-A is Pathogenic according to our data. Variant chr11-108353881-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127463.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.8786+1G>A		splice_donor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.8786+1G>A		splice_donor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152068

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251450

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135894

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000323

AC:

AN:

1456446

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

724990

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:

0.0000187

Gnomad4 NFE exome

AF:

0.0000406

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change affects a donor splice site in intron 60 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs17174393, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with a family history of breast cancer and ataxia-telangiectasia (PMID: 8659541, 8808599, 9463314, 10330348, 10817650, 10980530, 11298136, 21445571, 21459046, 21792198). This variant is also known as IVS62+1G>A and c.8672del115. ClinVar contains an entry for this variant (Variation ID: 127463). Studies have shown that disruption of this splice site results in skipping of exon 60 and/or activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 06, 2021	Variant summary: ATM c.8786+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. Multiple publications, Laake_2000 and Stankovic_1998, functionally assessed the variant and found it to affect mRNA splicing. The variant was observed with an allele frequency of 1.2e-05 in 246218 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.2e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.8786+1G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Laake_2000, Stankovic_1998). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Oct 27, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 22, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2019	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stankovic 1998, Garcia-Perez 2001, Reiman 2011); Observed in the heterozygous state in individuals with a personal or family history including lymphoma and colorectal cancer (Sutton 2015, AlDubayan 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS62+1G>A; This variant is associated with the following publications: (PMID: 8789452, 21445571, 25480502, 10330348, 9463314, 9443866, 10817650, 12552559, 11298136, 10980530, 8808599, 21792198, 8659541, 27479817, 29478780, 30338439, 30549301, 21459046, 25525159, 29625052, 31285527, 33436325, 30612635, 26681312, 31948886, 32853339, 26896183) -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2022	This variant causes a G to A nucleotide substitution at the +1 position of intron 60 of the ATM gene. RNA studies have shown that this variant causes the skipping of exon 60 (also known as exon 62 in the literature) or the inclusion of the first 14 nucleotides of intron 60 in the RNA transcripts (PMID: 9463314, 10330348, 10980530, 11298136). Both aberrant transcripts are expected to create a frameshift and premature truncation and result in an absent or non-functional protein product. This variant (also known as IVS62+1G>A in the literature) has been reported in many individuals affected with ataxia telangiectasia (PMID: 9463314, 10330348, 10817650, 10980530, 11298136, 12552559, 21792198). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 2/53461 controls (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991). This variant has also been identified in 4/251450 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2023	The c.8786+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after intron 59 of the ATM gene. This alteration has been detected in numerous individuals with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Schon K et al. Ann. Neurol. 2019 02;85(2):170-180). In addition, western blot analysis has shown that this alteration results in a truncated ATM protein product (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31). 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). 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 15, 2021	- -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 12, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Jan 25, 2024	The ATM c.8786+1G>A variant occurs within the canonical splice donor site (+/- 1,2) of intron 60. It is predicted to cause skipping of a biologically-relevant-exon, resulting in a premature stop codon and nonsense mediated decay. The highest minor allele frequency in gnomAD v2.1.1 is 0.00003517 (4/113738) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in at least 6 individuals with Ataxia-Telangiectasia (PMID: 26896183, 10817650, 9463314). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_very strong) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 05, 2024	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Malignant glioma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Feb 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.40

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

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_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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over