rs587779846

Positions:

• chr11-108301759-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5_Supporting PVS1 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.5290del (p.Leu1764TyrfsTer12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least four individuals with Ataxia-Telangiectasia (PMIDs: 22649200, 10425038, 12552559, 18634022, 15928302, 10330348, 18634022, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001763 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_Strong, PM5_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA286887/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 1.77

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]

ATM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5290delC	p.Leu1764fs	frameshift_variant	35/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5290delC	p.Leu1764fs	frameshift_variant	35/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251112 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135710

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461406 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000207

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Leu1764Tyrfs*12) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 10330348, 10425038, 12552559, 16832357, 22649200, 26681312). ClinVar contains an entry for this variant (Variation ID: 127405). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2018	Variant summary: ATM c.5290delC (p.Leu1764TyrfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.5712dupA/p.Ser1905fsX25, c.5908C>T/p.Gln1970X). The variant allele was found at a frequency of 8.3e-06 in 121178 control chromosomes. c.5290delC has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Castellvi-Bev_1999, Sun_2002, Thompson_2005). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2022	This frameshift variant alters the translational reading frame of the ATM mRNA and causes the premature termination of ATM protein synthesis. The frequency of this variant in the general population, 0.000018 (2/113458 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with ataxia-telangiectasia (PMIDs: 10330348 (1999), 10425038 (1999), 12552559 (2003), 15928302 (2005), 22649200 (2012), and 26896183 (2016)) and breast cancer (PMIDs: 16832357 (2006), 26681312 (2015), and 28779002 (2017)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2024	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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with breast and/or ovarian and other cancers (PMID: 16832357, 28779002, 27153395, 26689913); Observed in individuals with ataxia telangiectasia (PMID: 26896183, 10330348, 12552559, 12072877, 10425038); This variant is associated with the following publications: (PMID: 10330348, 30197789, 29625052, 12552559, 9887333, 12072877, 16832357, 10425038, 26681312, 27153395, 24763289, 18634022, 20346647, 26689913, 28152038, 28843361, 28779002, 26896183, 32866655, 36451132, 35626031) -

Familial cancer of breast Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Jan 25, 2024	The c.5290del (p.Leu1764TyrfsTer12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least four individuals with Ataxia-Telangiectasia (PMIDs: 22649200, 10425038, 12552559, 18634022, 15928302, 10330348, 18634022, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001763 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_Strong, PM5_Supporting) -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 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	Baylor Genetics	Mar 28, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2021	The c.5290delC pathogenic mutation, located in coding exon 34 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 5290, causing a translational frameshift with a predicted alternate stop codon (p.L1764Yfs*12). This pathogenic mutation has been detected in an ataxia-telangiectasia (A-T) cell line and in individuals with A-T (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sun X et al. J. Pediatr. 2002 Jun;140:724-31; Thompson D et al. J. Natl. Cancer Inst. 2005 Jun;97:813-22; Carney EF et al. J Immunol, 2012 Jul;189:261-8). This mutation has also been reported in multiple breast and/or ovarian cancer families (Renwick A et al. Nat Genet, 2006 Aug;38:873-5; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Decker B et al. J Med Genet, 2017 11;54:732-741). In one study, this variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	Feb 17, 2023	This variant deletes 1 nucleotide in exon 35 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 reported in individuals affected with ataxia telangiectasia (PMID: 10330348, 10425038, 12552559, 18634022, 22649200). This variant has also been reported in individuals affected with breast cancer (PMID: 16832357, 19781682, 26681312, 28779002) and lung cancer (PMID: 28843361). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251112 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 03, 2022

- -

ATM-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2022

The ATM c.5290delC variant is predicted to result in a frameshift and premature protein termination (p.Leu1764Tyrfs*12). This variant has been reported in the heterozygous state in several individuals with breast cancer (See for example, Susswein et al. 2015. PubMed ID: 26681312, Supp. Table S1; Decker et al. 2017. PubMed ID: 28779002, Supp. Table S5) and at least one individual with lung adenocarcinoma (Lu et al. 2015. PubMed ID: 26689913, Supp. Table S2). This variant has also been reported in the biallelic state in individuals with ataxia telangiectasia (Sun et al. 2002. PubMed ID: 12072877). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108172486-TC-T). Frameshift variants in ATM are expected to be pathogenic. This variant is classified as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127405/). This variant is interpreted 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: rs587779846; hg19: chr11-108172486; COSMIC: COSV53749370; COSMIC: COSV53749370;