rs587782660

chr11-108244841-TCCTC-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.717_720del(p.Phe239LeufsTer15) 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. F239F) has been classified as Likely 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:4
• Conservation: PhyloP100: 3.76

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 11-108244841-TCCTC-T is Pathogenic according to our data. Variant chr11-108244841-TCCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 142709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108244841-TCCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.717_720del	p.Phe239LeufsTer15	frameshift_variant	7/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.717_720del	p.Phe239LeufsTer15	frameshift_variant	7/63		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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change creates a premature translational stop signal (p.Phe239Leufs*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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 16941484, 17124347, 19691550, 22213089, 23454770). This variant is also known as 717delCCTC. ClinVar contains an entry for this variant (Variation ID: 142709). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2018

This deletion of 4 nucleotides in ATM is denoted c.717_720delCCTC at the cDNA level and p.Phe239LeufsX15 (F239LfsX15) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTT[CCTC]AAGA. The deletion causes a frameshift which changes a Phenylalanine to a Leucine at codon 239, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.717_720delCCTC has been observed in both the compound heterozygous and homozygous states in individuals with Ataxia-telangiectasia (Cavalieri 2006, Magliozzi 2006, Verhagen 2009). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.717_720delCCTC pathogenic mutation, located in coding exon 6 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 717 to 720, causing a translational frameshift with a predicted alternate stop codon (p.F239Lfs*15). This alteration has been reported in numerous individuals with ataxia-telangiectasia (Cavalieri S et al. Hum. Mutat. 2006 Oct;27:1061; Magliozzi M et al. Dis. Markers 2006;22:257-64; Verhagen MM et al. Neurology 2009 Aug;73:430-7). Haplotype analyses have suggested a possible Sicilian founder effect (Chessa L et al. Ann. Hum. Genet. 2009 Sep;73:532-9). 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 10, 2024

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

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: rs587782660; hg19: chr11-108115568;