rs587776552

Positions:

• chr11-108270482-GGTAA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000051.4(ATM):​c.2839-579_2839-576del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108270482-GGTAA-G is Pathogenic according to our data. Variant chr11-108270482-GGTAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.2839-579_2839-576del		intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2839-579_2839-576del		intron_variant			NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change falls in intron 18 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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 11889466, 14695534; Invitae). 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 a deletion of 4 bp (GTAA) in intron 20, IVS20+1874delGTAA, and IVS20-579delAAGT. ClinVar contains an entry for this variant (Variation ID: 3043). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11889466, 14695534, 19773425; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	May 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2022	Variant summary: ATM c.2839-579_2839-576delAAGT is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: two predict the variant weakens a cryptic 5 prime donor site; two predict the variant abolishes a 5 prime splicing donor site. However, at least one publication reports experimental evidence that this variant affects mRNA splicing. The variant was absent in 152078 control chromosomes. c.2839-579_2839-576delAAGT has been reported in the literature in individuals affected with Ataxia-Telangiectasia. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jun 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2023	This variant causes a 4 base-pair deletion in intron 18 of the ATM gene and is described in the literature as 'a deletion of 4 bp (GTAA) in intron 20' (numbering based on the U33841 transcript) and 'IVS20-579del-AAGT'. RNA studies have shown that this variant disrupts a non-canonical U1 small nuclear ribonucleoprotein binding site resulting in the insertion of a 65 base-pair cryptic exon, which is predicted to cause a frameshift and premature stop codon (PMID: 11889466, 12815592, 14695534, 19773425). An allele-specific RT-PCR assay using cells from a carrier individual has shown that the mutant allele does not produce normal transcript (PMID: 11889466). This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 11889466, 12815592, 14695534, 22213089). Lymphoblastoid cell lines derived from two of these individuals showed radiosensitivity and a significant reduction in protein expression (PMID: 14695534). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 22, 2022	The c.2839-579_2839-576delAAGT intronic pathogenic mutation, located in intron 17 of the ATM gene, results from a deletion of 4 nucleotides within intron 17 of the ATM gene. This variant has been identified in multiple patients with Ataxia Telangiectasia in a compound heterozygous state with other pathogenic ATM variants; cell lines derived from these patients showed radiosensitivity and low or no detectable ATM protein (Mitui M et al. Hum. Mutat., 2003 Jul;22:43-50; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76; Pagani F et al. Nat. Genet., 2002 Apr;30:426-9; Pastor T et al. Nucleic Acids Res., 2009 Nov;37:7258-67). This variant results in the inclusion of 65 nucleotides of intron 17 leading to a predicted frameshift and premature termination codon (Pagani F et al. Nat. Genet., 2002 Apr;30:426-9; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 11, 2023	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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11889466, 12815592, 14695534, 22213089]. Functional studies indicate this variant impacts protein function [PMID: 11889466]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2023

Non-canonical splice site variant demonstrated to result in loss-of-function (Pagani et al., 2002; Kim et al., 2023); No data available from control populations to assess the frequency of this variant; Also known as IVS20-579delAAGT or IVS20-579_IVS20-576delAAGT; This variant is associated with the following publications: (PMID: 19823873, 19773425, 14695534, 31611883, 11889466, 22213089, 12815592, 37438524) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.66		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776552; hg19: chr11-108141209;