rs587779834

chr11-108284280-AG-A

Variant summary

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

The NM_000051.4(ATM):c.3802del(p.Val1268Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,613,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:34 O:1
• Conservation: PhyloP100: -0.00200

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 11-108284280-AG-A is Pathogenic according to our data. Variant chr11-108284280-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 127374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108284280-AG-A is described in Lovd as [Pathogenic]. Variant chr11-108284280-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3802del	p.Val1268Ter	frameshift_variant	26/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3802del	p.Val1268Ter	frameshift_variant	26/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152198 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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251154 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000883 AC: 129 AN: 1460936 Hom.: 0 Cov.: 30 AF XY: 0.0000894 AC XY: 65 AN XY: 726822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

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: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:34 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	Nonsense 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; Also known as 3801delG; This variant is associated with the following publications: (PMID: 16832357, 25077176, 10330348, 15039971, 29478780, 17124347, 30772474, 23585524, 19781682, 12497634, 25614872, 25037873, 8755918, 22585167, 26786923, 21787400, 27664052, 10864201, 9463314, 11606401, 18384426, 27433846, 27484032, 21445571, 21965147, 28652578, 28691344, 30306255, 9887333, 12815592, 28779002, 21665257, 26182300, 29915322, 29961768, 30303537, 29625052, 26689913) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ATM: PVS1, PS4:Moderate, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 20, 2016	This frameshift variant causes the premature termination of ATM protein synthesis. In the literature, it has been reported in individuals with breast or pancreatic cancer (PMID: 22585167 (2012), 21787400 (2011), 18384426 (2008), 11606401 (2001)) or in individuals and families with Ataxia-telangiectasia (PMID: 21965147 (2011), 17124347 (2006), 9887333 (1999), 9463314 (1998)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2019	DNA sequence analysis of the ATM gene demonstrated a 1 base pair deletion in exon 26, c.3802del. This sequence change results in the creation of a premature stop codon at amino acid position 1268, p.Val1268*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. This sequence change has been reported in the gnomAD database with a frequency of 0.0085% in Latino populations (dbSNP rs781357995). The p.Val1268* change has been described in the homozygous and compound heterozygous states in patients with ataxia telangiectasia (PMID: 8755918, 21965147). This pathogenic sequence change has previously been described in the heterozygous state in patients with breast, colon, pancreatic and prostate cancer (PMID: 29478780, 28779002, 21787400, 27433846, 22585167, 29961768). -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Ataxia-telangiectasia syndrome Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2018	Variant summary: ATM c.3802delG (p.Val1268X) 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 (e.g., p.Arg1466X and p.Ser1905fsX25). The variant allele was found at a frequency of 4e-05 in 276948 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.3802delG has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as both a homozygous and compound heterozygous allele, indicating the variant is very likely to be associated with disease. At least one publication reports functional data indicating the variant significantly impairs protein expression and kinase activity in patient cells (Carranza_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 11 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia, and families with various types of cancer (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Val1268*) 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 (rs765158119, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T), and breast cancer (PMID: 8755918, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 23585524, 25077176, 25614872). It is commonly reported in individuals of British Isles ancestry (PMID: 8755918, 9463314, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 22585167, 23585524, 25077176, 25614872). This variant is also known as c.3801delG. ClinVar contains an entry for this variant (Variation ID: 127374). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Familial cancer of breast Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 17, 2022	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 23, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1, PS3_MOD, PM3_VSTR -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 13, 2023	This variant deletes 1 nucleotide in exon 26 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 or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8755918, 9887333, 10864201, 21965147, 25077176, 25614872, 27664052, 34337741). This variant has also been reported in individuals affected with breast cancer (PMID: 16832357, 18384426, 21445571, 21787400), pancreatic cancer (PMID: 22585167), prostate cancer (PMID: 27433846, 33436325), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has been identified in 11/282542 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	clinical testing	Ambry Genetics	Apr 05, 2022	The c.3802delG pathogenic mutation, located in coding exon 25 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3802, causing a translational frameshift with a predicted alternate stop codon (p.V1268*). This alteration has been reported in breast cancer, pancreatic cancer, prostate cancer, colorectal cancer and ataxia-telangiectasia (AT) families to date (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Roberts NJ et al. Cancer Discov. 2012 Jan;2:41-6; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; AlDubayan SH et al. Am. J. Hum. Genet. 2018 Mar;102:401-414; Yurgelun MB et al. Genet. Med. 2019 Jan;21:213-223). 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	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.3802del (p.Val1268*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0034%, (9/268,016 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0086%, (3/35,074 alleles) in the the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been reported in at least eighteen ataxia-telangiectasia probands in homozygosis or together with (likely) pathogenic variants, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong; PMID: 27664052, 10330348, 12815592, 21665257, 21965147, 8755918, 9887333). Moreover, lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no detectable ATM p.Ser1981 autophosphorylation, weak transphosphorylation activity of two substrates and intermediate or high radiosensitivity (PS3; PMID: 10864201, 27664052, 25077176). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3 (PMID: 33280026). -

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

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant classified as Pathogenic and reported on 01-28-2018 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 13, 2021	- -

ATM-related cancer predisposition syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2023

The ATM c.3802del (p.Val1268Ter) nonsense variant, also referred to as c.3801delG, is expected to result in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Across a selection of the available literature, this variant has been identified in trans with a likely pathogenic or pathogenic ATM variant in multiple individuals with a diagnosis of ataxia-telangiectasia, including at least one individual whose cells showed evidence of reduced protein expression and kinase activity (PMID: 8755918; 9887333; 25614872; 27664052). In addition, truncating variants in ATM, including the p.Val1268Ter variant, have been associated with an increased risk of breast cancer (OR=3.26; 95% CI 1.82-6.46). This variant has also been reported as a germline variant in individuals with pancreatic, prostate, and other cancers (PMID: 29922827; 28779002; 33436325). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000088 in the European (non-Finnish) population (version 3.1.2) and has been classified as pathogenic by at least 28 submitters in ClinVar. Based on the collective evidence, the c.3802del (p.Val1268Ter) variant is classified as pathogenic for ATM-related cancer predisposition syndrome. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 03, 2020

- -

ATM-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The ATM c.3802delG variant is predicted to result in premature protein termination (p.Val1268*). This variant has been reported in the homozygous or compound heterozygous states in several individuals with ataxia telangiectasia (McConville et al. 1996. PubMed ID: 8755918; Stankovic et al. 1998. PubMed ID: 9463314; Sandoval et al. 1999. PubMed ID: 9887333; Podralska et al. 2014. PubMed ID: 25614872), and individuals with breast and pancreatic cancer (Dörk et al. 2001. PubMed ID: 11606401; Roberts et al. 2012. PubMed ID: 22585167). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127374/?new_evidence=true). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial pancreatic carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Val1268X variant was identified in 9 of 8368 proband chromosomes (frequency: 0.001) from Spanish, British, Australian and North American individuals or families with BRCA1/2 negative breast cancer, metastatic prostate cancer, or pancreatic cancer and was not identified in 2972 control chromosomes from healthy individuals (Brunet 2008 PMID:18384426, Goldgar 2011 PMID:21787400, Grana 2011 PMID:21445571, Pritchard 2016 PMID:27433846, Renwick 2006 PMID:16832357, Roberts 2012 PMID:22585167). The variant was also identified in dbSNP (ID: rs765158119, currently merged with rs587779834) “With Pathogenic allele”, ClinVar (classified pathogenic by GeneDx, Ambry Genetics, Invitae, Counsyl and Color Genomics Inc.), Clinvitae (3x), Cosmic (1x in lymphoid neoplasm), LOVD 3.0 (1x in lymphoid neoplasm), and was not identified in GeneInsight-COGR, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3802delG variant leads to a premature stop codon at position 1268 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 19, 2021

Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive -

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: rs587779834; hg19: chr11-108155007;