rs587781971

chr11-108279586-CTCAG-C

Variant summary

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

The NM_000051.4(ATM):c.3381_3384del(p.Gln1128LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1127A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.48

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 11-108279586-CTCAG-C is Pathogenic according to our data. Variant chr11-108279586-CTCAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141734.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.3381_3384del	p.Gln1128LysfsTer3	frameshift_variant	23/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3381_3384del	p.Gln1128LysfsTer3	frameshift_variant	23/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	This sequence change creates a premature translational stop signal (p.Gln1128Lysfs*3) 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: 10425038). This variant is also known as 3381delTCAG. ClinVar contains an entry for this variant (Variation ID: 141734). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2023	This variant, also referred to as '3381delTCAG', deletes 4 nucleotides in exon 23 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. This variant has been observed in an individual affected with ataxia telangiectasia, however, the report did not mention a second mutation (PMID: 10425038). This variant was reported in an individual diagnosed with breast cancer at 33 years old who carried a second pathogenic variant in BRCA2 (PMID: 26976419) and an individual affected with prostate cancer (DOI: 10.1097/JU.0000000000003186). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2020	The c.3381_3384delTCAG pathogenic mutation, located in coding exon 22 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 3381 to 3384, causing a translational frameshift with a predicted alternate stop codon (p.Q1128Kfs*3). This pathogenic mutation (designated as 3381delTCAG) was reported in an individual with ataxia-telangiectasia, although it was not noted whether a second mutation was identified (Castellví-Bel S et al. Hum. Mutat. 1999; 14(2):156-62). This mutation was also observed in conjunction with a BRCA2 pathogenic mutation in an individual diagnosed with breast cancer at age 33 who had a family history of breast, pancreatic, thyroid and esophageal cancer (Tung N et al. J. Clin. Oncol. 2016 May; 34(13):1460-8). 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. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 25, 2021	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 22, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2023

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 at significant frequency in large population cohorts (gnomAD); Identified in an individual with a personal history of breast cancer and family history of breast, pancreatic, and other cancers who also harbored a pathogenic BRCA2 variant (Tung et al., 2016); Identified in an individual with ataxia telangiectasia for whom clinical and other testing details are limited (Castellvi-Bel et al., 1999); This variant is associated with the following publications: (PMID: 28152038, 27304073, 26976419, 23807571, 25614872, 36974724, 30625039, 10425038) -

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: rs587781971; hg19: chr11-108150313;