rs587776549

chr11-108272812-CATC-CTGAT

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.3245_3247delinsTGAT(p.His1082LeufsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:2
• Conservation: PhyloP100: 7.50

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 11-108272813-ATC-TGAT is Pathogenic according to our data. Variant chr11-108272813-ATC-TGAT is described in ClinVar as [Pathogenic]. Clinvar id is 3033.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3245_3247delinsTGAT	p.His1082LeufsTer14	frameshift_variant	22/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3245_3247delinsTGAT	p.His1082LeufsTer14	frameshift_variant	22/63		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

Submissions summary: Pathogenic:16 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 19, 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	Division of Medical Genetics, University of Washington	Mar 09, 2020	The variant causes a frameshift and creates a premature stop codon at position 14 of the new reading frame. The variant transcript is predicted to be degraded by nonsense-mediated decay or lead to a truncated protein. Loss of expression of one allele of ATM is a well-established mechanism of disease (Huang 2013, Podralska 2014). This variant has been reported in the literature in individuals with breast or prostate cancer (Vorechovsky 2996, Chen 1998, Hart 2016) and in individuals with ataxia-telangiectasia (Telatar 1998, Laake 1998, Laake 2000). This variant has an allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PVS1; PM3 -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.3245_3247delinsTGAT (p.His1082LeufsTer14) variant is absent in the GnomAD cohort (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.His1082Leufs*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). This variant is present in population databases (rs761486324, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia, breast cancer, and/or prostate cancer (PMID: 8797579, 9443866, 9537233, 9781027, 10980530, 27084275). It is commonly reported in individuals of Norwegian ancestry (PMID: 9443866, 9781027, 10980530). ClinVar contains an entry for this variant (Variation ID: 3033). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2017	Variant summary: The ATM c.3245_3247delinsTGAT (p.His1082LeufsX14) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 30972 control chromosomes (gnomAD). Multiple publications have cited the variant in affected A-T patients and has been indicated to be a Norwegian founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2016	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	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; Observed in the heterozygous state in individuals with a personal history of ATM-related cancers (Vorechovsky 1996, Brand 2018, Dominguez-Valentin 2019, Borazanci 2020); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26681312, 17540590, 15196260, 15942625, 9443866, 18321536, 9781027, 8797579, 9537233, 30067863, 27084275, 10817650, 10980530, 31391296, 31811167, 30612635, 33763108, 33144682) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 28, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 09-04-2019 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 04, 2023	This variant replaces 3 nucleotides in exon 22 of the ATM gene with 4 new nucleotides, 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 reported in individuals affected with ataxia-telangiectasia and is a recurrent mutation in the Norwegian population (PMID: 9443866, 9781027, 10980530). This variant has also been reported in individuals affected with breast cancer (PMID: 8797579, 9537233, 11104561, 31882575), prostate cancer (PMID: 27084275), and ovarian cancer (PMID: 31882575). 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	Apr 22, 2022	The c.3245_3247delATCinsTGAT pathogenic mutation, located in coding exon 21 of the ATM gene, results from the deletion of 3 nucleotides (ATC) and insertion of 4 nucleotides (TGAT) at positions 3245 to 3247, causing a translational frameshift with a predicted alternate stop codon (p.H1082Lfs*14). This mutation has been detected in both the homozygous and compound heterozygous state in multiple patients with ataxia-telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Stray-Pedersen A et al. Eur. J. Paediatr. Neurol. 2007 Nov;11:375-80). In addition, this mutation has been described as a Norwegian founder mutation and accounted for greater than 50% of pathogenic ATM alleles detected in one series of Norwegian A-T families (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46). This mutation was also detected in two individuals with histories of breast cancer and/or pilocytic astrocytoma (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 09, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 11-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Jun 17, 2019

The c.3245_3247delATCinsTGAT (p.His1082Leufs*14) variant in the ATM gene creates a stop codon which is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant is absent from general population databases. Therefore, this c.3245_3247delATCinsTGAT (p.His1082Leufs*14) variant in the ATM gene is classified as pathogenic. -

ATM-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

The ATM c.3245_3247delinsTGAT variant is predicted to result in a frameshift and premature protein termination (p.His1082Leufs*14). This variant has been reported in individuals with autosomal recessive ataxia telangiectasia (Table 2, referred to as 3245ATC>TGAT, Telatar et al. 1998. PubMed ID: 9443866). It has also been reported in individuals with breast cancer, pilocytic astrocytoma, and pancreatic cancer (Table 2, referred to as 3246insG, Vorechovský et al. 1996. PubMed ID: 8797579; Table S1, Susswein et al. 2015. PubMed ID: 26681312; eTable 3, Hu et al. 2018. PubMed ID: 29922827; Table 2, Brand et al. 2018. PubMed ID: 30067863). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://preview.ncbi.nlm.nih.gov/clinvar/variation/3033/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776549; hg19: chr11-108143540;