rs1057516282

chr11-108365400-A-AG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000051.4(ATM):c.9064dup(p.Glu3022GlyfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E3021E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.52

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 14 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 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365400-A-AG is Pathogenic according to our data. Variant chr11-108365400-A-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370165.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.9064dup	p.Glu3022GlyfsTer41	frameshift_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.9064dup	p.Glu3022GlyfsTer41	frameshift_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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 Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change results in a frameshift in the ATM gene (p.Glu3022Glyfs*41). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the ATM protein and extend the protein by 5 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with ataxia-telangiectasia (PMID: 12552559). ClinVar contains an entry for this variant (Variation ID: 370165). This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 10980530, 18560558, 19691550, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2022	This variant inserts 1 nucleotide in exon 63 of the ATM gene, creating a frameshift in the last coding exon and extending the length of the ATM protein by 5 amino acids. This variant is expected to alter the FATC domain and disrupt the ATM protein function (PMID: 16603769). This variant has been observed in the compound heterozygous state in an individual affected with autosomal recessive ataxia-telangiectasia (PMID: 12552559), indicating that this variant contributes to disease. 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2021	The c.9064dupG pathogenic mutation, located in coding exon 62 of the ATM gene, results from a duplication of G at nucleotide position 9064, causing a translational frameshift with a predicted alternate stop codon (p.E3022Gfs*41). This pathogenic mutation was reported in the literature in a compound heterozygous state with a consensus splice site alteration, IVS20+1G>A, in a patient with ataxia telangiectasia (Buzin CH et al. Hum. Mutat. 2003 Feb;21(2):123-31). In another study, this mutation was reported in one out of 188 chronic lymphocytic leukemia patients with poor-prognostic features who also showed a typical immunophenotype (Sutton LA et al. Haematologica. 2015 Mar;100(3):370-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Familial cancer of breast Pathogenic:1

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: 12552559, 16266405, 25614872, 15039971, 21965147]. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057516282; hg19: chr11-108236127;