rs786203796

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.5497-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000186 in 1,613,248 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.17

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 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.

PM2

Very rare variant in population databases, with high coverage;

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 11-108304673-A-C is Pathogenic according to our data. Variant chr11-108304673-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5497-2A>C		splice_acceptor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.5497-2A>C		splice_acceptor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461084

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726890

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

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

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 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. -
Pathogenic, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 08, 2023	Criteria applied: PVS1,PS3_mod, PS4_mod, PM2_sup -
Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 28, 2022	The ATM c.5497-2A>C intronic change results from a A to C substitution at the -2 position of intron 36 of the ATM gene. RNA studies have shown that this variant causes abnormal splicing which results in frameshift and premature protein truncation (PMID: 10330348, internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org) and is not reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). This variant has been observed in the heterozygous state in an individual with ataxia-telangiectasia, however a second variant was not identified (PMID: 10330348). In summary, this variant meets criteria to be classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -

Ataxia-telangiectasia syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change affects an acceptor splice site in intron 36 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 10330348). This variant is also known as IVS38-2A>C. ClinVar contains an entry for this variant (Variation ID: 449345). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10330348, 31843900; 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	MGZ Medical Genetics Center	Dec 10, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2023	Canonical splice site variant demonstrated to result in a null allele through the use of cryptic splice site leading to premature stop codon in a gene for which loss of function is a known mechanism of disease (Teraoka et al., 1999; Casadei et al., 2019); Observed in individuals with early onset breast cancer and other cancers (Renault et al., 2018; Casadei et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS38-2A>C; This variant is associated with the following publications: (PMID: 31589614, 34687117, 26837699, 25525159, 30303537, 31843900, 10330348, 29665859) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 29, 2023	The c.5497-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the ATM gene. This mutation (designated as IVS38-2A>C) was reported in an individual diagnosed with ataxia-telangiectasia (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31; Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This variant (also known as IVS38-2A>C in the literature) causes an A to C nucleotide substitution at the -2 position of intron 36 of the ATM gene. RNA studies have shown that this variant causes the deletion of the first 61 nucleotides of exon 37 in the RNA transcript, creating a frameshift and premature translation stop signal (PMID: 10330348, 14695534, 31843900). The aberrant RNA transcript is expected to result in an absent or disrupted protein product. This variant has been reported in the homozygous state or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 10330348, 14695534, 21665257). This variant has also been reported in an individual affected with breast cancer (PMID: 32125938). This variant has not been identified 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. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Jan 08, 2024

Found compound heterozygous in AT patient. According to the ACMG standard criteria we chose these criteria: PVS1 (very strong pathogenic): ClinGen Interpretation Guidelines for ATM Version 1.1: PVS1_very strong [experimental data for NMD (list A)] The c.5497-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the ATM gene, PS3 (strong pathogenic): RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec, Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31, and Ambry Genetics internal data)., PM2 (supporting pathogenic): ClinGen Interpretation Guidelines for ATM Version 1.1: PM2_supporting [absent/rare from controls] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 23

DS_AL_spliceai

0.98

Position offset: 2

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