11-108365356-G-T

Variant names:

• chr11-108365356-G-T
• rs876660382
• NM_000051.4:c.9019G>T

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.9019G>T​(p.Glu3007*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365356-G-T is Pathogenic according to our data. Variant chr11-108365356-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108365356-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.9019G>T	p.Glu3007*	stop_gained	Exon 63 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.9019G>T	p.Glu3007*	stop_gained	Exon 63 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Aug 06, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.9019G>T at the cDNA level and p.Glu3007Ter (E3007X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Due to the position of the variant, nonsense mediated decay is not expected to occur, but it is predicted to cause loss of normal protein function through protein truncation as the last 49 amino acids are no longer translated. The disrupted region at the end of the gene is located within the FATC domain (Stracker 2013). This variant has been reported in an individual with Ataxia-telangiectasia and in at least two individuals with breast cancer (Broeks 1998, Tung 2015, Hauke 2018). We consider ATM Glu3007Ter to be a likely pathogenic variant. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Pathogenic:2

Apr 29, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu3007*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the ATM protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9792409, 25186627). ClinVar contains an entry for this variant (Variation ID: 233403). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). 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, 19431188, 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

Feb 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E3007* pathogenic mutation (also known as c.9019G>T), located in coding exon 62 of the ATM gene, results from a G to T substitution at nucleotide position 9019. This changes the amino acid from a glutamic acid to a stop codon within coding exon 62. This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 50 amino acids of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in a compound heterozygous state in a Dutch individual with ataxia telangiectasia (Broeks A et al. Hum. Mutat. 1998;12:330-7). This alteration has also been reported in a breast cancer patient undergoing multi-gene panel testing (Tung N et al. Cancer. 2015 Jan 1;121(1):25-33), in 1/535 pancreatic ductal adenocarcinoma patients (Zimmermann MT et al. Front Oncol, 2021 Mar;11:606820), and in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). 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 alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Apr 27, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 63 of the ATM gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape the nonsense-mediated decay and be expressed as a truncated protein, this C-terminally truncated protein is expected to disrupt the TP53 binding domain and FATC domain and to affect normal ATM protein function (PMID: 19779456). In addition, a truncating variant (p.Arg3047*) occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 3029), suggesting that the truncated region is important for protein structure and function. This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 9792409). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 29522266). 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. -

Clear cell carcinoma of kidney Pathogenic:1

Mar 23, 2022

Michigan Center for Translational Pathology, University of Michigan

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

ATM c.9019G>T; p.E3007* noted in a 36 year old female with aggressive, metastatic RCC and a significant family history of cancer (including father diagnosed with RCC at age 59, who died of rapidly progressive disease) with the tumor showing somatic loss of heterozygosity (LOH) by uniparental disomy. The substitution in ATM induces a nonsense variant, which truncates the final 49 amino acid residues from the C-terminal, expected to disrupt the TP53 binding domain and FATC domain and to affect normal ATM protein function (PMID: 19779456). Ataxia telangiectasia mutated gene (ATM) plays a critical role in DNA repair and response to double strand breaks. ATM is associated with increased risk of breast cancer, pancreatic cancer and prostate cancer. -

Familial cancer of breast Pathogenic:1

Feb 06, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.81
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: -31

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660382; hg19: chr11-108236083;