rs876659535

Positions:

• chr11-108293338-TGATA-T

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.4642_4645del​(p.Asp1548ThrfsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V1546V) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.07

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108293338-TGATA-T is Pathogenic according to our data. Variant chr11-108293338-TGATA-T is described in ClinVar as [Pathogenic]. Clinvar id is 232070.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.4642_4645del	p.Asp1548ThrfsTer14	frameshift_variant	31/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4642_4645del	p.Asp1548ThrfsTer14	frameshift_variant	31/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

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	DASA	Aug 10, 2022	The c.4642_4645del;p.(Asp1548Thrfs*14) is a null frameshift variant (NMD) in the ATM gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 232070; PMID: 9711876; 8808599) - PS4. This variant is not present in population databases (rs876659535- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The p.(Asp1548Thrfs*14) was detected in trans with a pathogenic variant (PMID: 9711876; 8808599) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 232070). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8808599, 9711876). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp1548Thrfs*14) 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). -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Asp1548Thrfs*14 variant was identified in 1 of 180 proband chromosomes (frequency: 0.006) from individuals or families with Ataxia Telangiectasia (Li 2000) and in lymphoblastoid cell lines or skin fibroblasts of patients with Ataxia Telangiectasia (Sasaki 1998, Wright 1996). The variant was also identified in dbSNP (ID: rs876659535) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae and Ambry Genetics), and LOVD 3.0 (2x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.4642_4645del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1548 and leads to a premature stop codon at position 1561. 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2022

The c.4642_4645delGATA pathogenic mutation, located in coding exon 30 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 4642 to 4645, causing a translational frameshift with a predicted alternate stop codon (p.D1548Tfs*14). This alteration, referred to as a deletion of GATA at nucleotide 4638 or 4638del4, was detected as a compound heterozygous mutation in multiple individuals with ataxia-telangiectasia (Wright J et al. Am J Hum Genet. 1996 Oct;59(4):839-46; Li A et al. Am J Med Genet. 2000 May 29;92(3):170-7). 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. -

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: rs876659535; hg19: chr11-108164065;