rs587781347

Positions:

chr11-108250866-CAA-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5_SupportingPVS1PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.1402_1403del (p.Lys468Glufs*18) variant in ATM is a frameshift variant in a biologically-relevant-exon predicted to cause a premature stop codon 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 3 individuals with Ataxia-Telangiectasia (PMID:23807571, 26896183, 31691010). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003 in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. (PVS1, PM5_Supporting, PM3_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA163840/MONDO:0700270/020

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATM
NM_000051.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:21

Conservation

PhyloP100: 2.79

Variant links:

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 links:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1402_1403delAA	p.Lys468fs	frameshift_variant	10/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.1402_1403delAA	p.Lys468fs	frameshift_variant	10/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251414

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461852

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 18, 2015	This frameshift variant causes the premature termination of ATM protein synthesis. In addition, it has been reported in individuals affected with breast and ovarian cancer, as well as ataxia-telangiectasia, in the published literature (PMID: 31815095 (2019), 26094658 (2015), 20308662 (2010), 9792409 (1998)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing ATM related cancers. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 23322442, 22649200, 25892863, 26094658, 20308662, 32866655, 24733792, 10817650, 9792409, 12552559, 23807571, 24763289, 23264026, 21933854, 23726790, 25101980, 27433846, 28779002, 28152038, 30322717, 30607632, 31815095, 32318955, 31447099, 31980526, 26896183, 31691010, 32761968, 34247626, 21665257, 35171259, 34771502, 34917121, 33277227, 30613976, 28724667, 29922827) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 08, 2023	PM3_strong, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ataxia-telangiectasia syndrome

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000140889 / PMID: 9792409). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2020	Variant summary: ATM c.1402_1403delAA (p.Lys468GlufsX18) 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. The variant allele was found at a frequency of 4e-05 in 251414 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.1402_1403delAA has been reported in the literature in homozygous and compound heterozygous genotypes among multiple individuals affected with Ataxia-Telangiectasia (example, Broeks_1998, Lin_2010, Buzin_2003, Carney_2012, Jeddane_2013), and in heterozygosity among multiple individuals with a variety of cancers, such as breast and ovarian (example, Kurian_2015, Alorafi_2015, Manchana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Carney_2012). The most pronounced variant effect results in a complete absence of ATM protein as measured by western blot and no ATM activity. Four 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 (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Lys468Glufs*18) 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 (rs587781347, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast, rectal, prostate or ovarian cancer (PMID: 9792409, 12552559, 20308662, 22649200, 23322442, 24733792, 25892863, 26094658, 27433846, 30322717, 31815095). ClinVar contains an entry for this variant (Variation ID: 140889). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 16, 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 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 04, 2024	The ATM c.1402_1403del (p.Lys468GlufsTer18) change deletes two nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in the homozygous and compound heterozygous state in individuals with ataxia telangiectasia (PMID 9792409; 12552559; 20308662; 21665257; 22649200; 23322442; 23726790; 23807571). This variant has a maximum subpopulation frequency of 0.03% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 28, 2022	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM3 -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 26, 2022	PVS1, PS3_Moderate, PS4_Moderate (for AD cancer risk) or PM3_VeryStrong (for AR ataxia-telangiectasia), PM2 (for AR only) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2012	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense) -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 04, 2023	This variant deletes 2 nucleotides in exon 10 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 the homozygous state and in the compound heterozygous state with an additional ATM pathogenic variant in individuals affected with ataxia telangiectasia (PMID: 9792409, 20308662, 21665257, 22649200, 23322442, 23726790, 23807571). This variant has also been reported in individuals affected with breast cancer and ovarian cancer (PMID: 24733792, 26094658, 31815095). This variant has been identified in 13/282780 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. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 03, 2022

- -

ATM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The ATM c.1402_1403delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys468Glufs*18). This variant has previously been reported in individuals with autosomal recessive ataxia telangiectasia (Broeks et al. 1998. PubMed ID: 9792409; Lin et al. 2010. PubMed ID: 20308662), breast cancer (Kurian et al. 2014. PubMed ID: 24733792; Aloraifi et al. 2015. PubMed ID: 26094658), and non-polyposis colorectal cancer (Zhang et al. 2015. PubMed ID: 25892863). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140889/). Frameshift variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over