rs587781653

chr11-108289736-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):c.4373del(p.Gly1458GlufsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.61

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108289736-AG-A is Pathogenic according to our data. Variant chr11-108289736-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 141315.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.4373del	p.Gly1458GlufsTer15	frameshift_variant	29/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4373del	p.Gly1458GlufsTer15	frameshift_variant	29/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251220 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461452 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727024

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jul 07, 2023	This sequence change in ATM is a frameshift variant predicted to cause a premature stop codon, p.(Gly1458Glufs*15), in biologically relevant exon 29/63 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is present in a single individual from the European (non-Finnish) population in the population database gnomAD v2.1 (1/113,616 alleles). This variant has been reported in one individual with prostate cancer and a patient referred for cancer panel testing (PMID: 26681312, 32694154). This variant has been detected compound heterozygous with a second variant in at least three individuals with a clinical diagnosis of ataxia telangiectasia (PMID: 10330348, 18321536, 22649200). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 20, 2020	ACMG codes:PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Gly1458Glufs*15) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs587781653, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with prostate cancer and ataxia-telangiectasia (PMID: 10330348, 22649200, 27433846). ClinVar contains an entry for this variant (Variation ID: 141315). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 24, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 30, 2017	The c.4373delG frame shift variant is predicted to yield loss of function transcripts/proteins of ATM gene, which is one of mechanisms causing Ataxia-telangiectasia. This variant is extremely rare in general population (1 in 246014 by gnomad) and observed in multiple ataxia-telangiectasia patients (PMID:10330348, 22649200). It has been also observed in other clinical labs and reported as a pathogenic. Based on the above evidences, we interpret this variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26681312, 10330348, 10817650, 22649200, 27433846, 31447099, 31948886) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Gly1458Glufs*15 variant was identified in 5 of 7742 proband chromosomes (frequency: 0.0005) from individuals or families with Ataxia-telangiectasia, prostate cancer, and pancreatic cancer (Carney 2012, Li 2000, Pritchard 2016, Teraoka 1999, Hu 2018). The variant was also identified in dbSNP (ID: rs587781653) as “With Pathogenic allele”, ClinVar (as pathogenic by Ambry Genetics, GeneDx, and Invitae), Clinvitae (3x), and the ATM-LOVD (2x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 1 of 246014 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the European (Non-Finnish) population in 1 of 111568 chromosomes (freq: 0.000009), but not in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, Other, and South Asian populations. The p.Gly1458Glufs*15 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1458 and leads to a premature stop codon at position 1472. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM-associated Cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2021	The c.4373delG pathogenic mutation, located in coding exon 28 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 4373, causing a translational frameshift with a predicted alternate stop codon (p.G1458Efs*15). This mutation has been reported in several patients with classic ataxia-telangiectasia (Teraoka SN et al. Am. J. Hum. Genet. 1999; 64:1617-31, Li A et al. Am J Med Genet. 2000 May 29;92(3):170-7; Du L et al. Mutat Res, 2008 Apr;640:139-44; Carney EF et al. J Immunol, 2012 Jul;189:261-8). This mutation was also detected in men diagnosed with prostate cancer (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53; Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230). 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 14, 2020	This variant deletes 1 nucleotide in exon 29 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals affected with ataxia telangiectasia including compound heterozygous and homozygous carriers (PMID: 10330348, 10817650, 22649200). This variant has been identified in 1/251220 chromosomes 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. -

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: rs587781653; hg19: chr11-108160463;