rs786203796

Variant names:

• chr11-108304673-A-C
• rs786203796
• NM_000051.4:c.5497-2A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108304673-A-C
• chr11-108304673-A-G
• chr11-108304673-A-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.5497-2A>C variant causes a splice acceptor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.17
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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
• PP5: Variant 11-108304673-A-C is Pathogenic according to our data. Variant chr11-108304673-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449345.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	c.5497-2A>C		splice_acceptor_variant, intron_variant	Intron 36 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5497-2A>C		splice_acceptor_variant, intron_variant	Intron 36 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

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: 2 AN: 1461084 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111440

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Jan 25, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 08, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS3_mod, PS4_mod, PM2_sup -

Feb 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Ataxia-telangiectasia syndrome Pathogenic:3

Dec 11, 2017

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. -

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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 (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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 10330348, 31843900; internal data). For these reasons, this variant has been classified as Pathogenic. -

Dec 10, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Oct 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.5497-2A>C variant disrupts a canonical splice-acceptor site and interferes with normal ATM mRNA splicing. This variant has been reported in the published literature in individuals with breast cancer (PMID: 32125938 (2020)) and ataxia-telangiectasia (PMIDs: 21665257 (2011), 14695534 (2004), 10330348 (1999)). The frequency of this variant in the general population, 0.0000066 (1/152164 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 29, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 08, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.2
GERP RS		5.5
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs786203796; hg19: chr11-108175400; COSMIC: COSV108078982;