rs876660235

Positions:

• chr11-108365356-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.9021dup​(p.Arg3008ThrfsTer55) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E3007E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.08

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365356-G-GA is Pathogenic according to our data. Variant chr11-108365356-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233164.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	c.9021dup	p.Arg3008ThrfsTer55	frameshift_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.9021dup	p.Arg3008ThrfsTer55	frameshift_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16266405, 25614872, 15039971, 21965147]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Oct 25, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 05, 2022	The c.9021dupA pathogenic mutation, located in coding exon 62 of the ATM gene, results from a duplication of A at nucleotide position 9021, causing a translational frameshift with a predicted alternate stop codon (p.R3008Tfs*55). Functional analysis of a lymphoblastoid cell line derived from a compound heterozygous patient with ataxia telangiectasia (AT) suggests this alteration results in deficient ATM protein and a double-strand break repair pattern resembling MRN-complex dysfunction. Authors note that the individual from whom this cell line was derived was older than 60 years with an attenuated or variant form of AT with moderate radiosensitivity, chromosomal instability, and cancer proneness (Keimling M et al. FASEB J. 2011 Nov; 25(11):3849-60). An individual with classic ataxia-telangiectasia was found to be homozygous for this mutation (designated 9021_9022insA, p.Arg3008ThrfsTer54) with the diagnosis confirmed by absence of ATM protein by immunoblotting in lymphoblastoid cell lines and radiosensitivity demonstrated on a colony survival assay (Podralska MJ et al. Mol Genet Genomic Med, 2014 Nov;2:504-11; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69:657-64). In addition to the clinical data presented in the literature, this frameshift occurs near the 3' terminus of ATM and results in the elongation of the protein by 6 amino acids. This mutation alters the sequence of the FATC domain of the ATM protein which has been shown to be necessary for ATM regulation (Jiang XJ et al. Biol. Chem. 2006 Jun;281(23):15741-6). As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2020	This variant inserts 1 nucleotide in exon 63 of the ATM gene, creating a frameshift in the last exon. This variant is also known as c.9021_9022insA in the literature. This variant alters the C-terminus of the TP53 binding domain and FATC domain sequence and is expected to disrupt ATP protein function. This variant has been reported in two biallelic individuals affected with 2 ataxia-telangiectasia (PMID: 21778326, 25614872). 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. -

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg3008 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12552566, 15101044, 18573109, 22649200). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this frameshift affects ATM function (PMID: 21778326). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This frameshift has been observed in individual(s) with ataxia-telangiectasia (PMID: 21778326). This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the ATM gene (p.Arg3008Thrfs*55). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the ATM protein and extend the protein by 5 additional amino acid residues. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2017

This duplication of one nucleotide in ATM is denoted c.9021dupA at the cDNA level and p.Arg3008ThrfsX55 (R3008TfsX55) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTGA[dupA]CGTG. The duplication causes a frameshift, which changes an Arginine to a Threonine at codon 3008, and creates a premature stop codon at position 55 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 49 amino acids are replaced with 54 incorrect amino acids and impacts the FATC domain (Stracker 2013). ATM Arg3008ThrfsX55 has been observed in the homozygous state in a patient with classic Ataxia Telangiectasia, whose lymphoblastoid cell line exhibited radiosensitivity and absence of ATM protein production (Mitui 2005, Podralska 2014). We consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660235; hg19: chr11-108236083;