GeneBe

rs587779818

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000051.4(ATM):​c.170G>A​(p.Trp57*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,611,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ATM
NM_000051.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 8.59
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]

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ACMG classification

Classification made for transcript

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 11-108227873-G-A is Pathogenic according to our data. Variant chr11-108227873-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATMNM_000051.4 linkuse as main transcriptc.170G>A p.Trp57* stop_gained 3/63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.170G>A p.Trp57* stop_gained 3/63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151962
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1459892
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726298
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000990
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151962
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 29, 2022- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 13, 2020Variant summary: ATM c.170G>A (p.Trp57X) 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. The variant was absent in 250818 control chromosomes (gnomAD). c.170G>A has been reported in the literature in multiple compound heterozygous individuals, who were affected with the classic- or variant form of Ataxia-Telangiectasia (Li_2000, Nahas_2009, Schon_2019). The variant was also found in heterozygous individuals affected with various tumor phenotypes, e.g. pancreatic cancer (Roberts_2012, Shindo_2017), where the variant was reported to segregate with the disease in one family (Roberts_2012). These data indicate that the variant is likely to be associated with disease. Seven 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. -
Pathogenic, criteria provided, single submitterclinical testingCounsylNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This sequence change creates a premature translational stop signal (p.Trp57*) 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, breast cancer, multiple sessile serrated adenomas, colon cancer, and pancreatic cancer (PMID: 10817650, 21787400, 22585167, 24512911, 26681312, 27083775). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127341). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 12, 2017- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsMay 21, 2018- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 16, 2024Nonsense 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 and/or family history of breast, pancreatic, or colorectal cancer (PMID: 19781682, 21787400, 22585167, 27083775, 27276934, 27978560, 30716324); 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; This variant is associated with the following publications: (PMID: 28152038, 25525159, 30549301, 29922827, 28888541, 24512911, 10817650, 19781682, 21787400, 20346647, 26681312, 27276934, 27153395, 27083775, 22585167, 27978560, 28767289, 30716324, 31447099, 32853339, 19147735, 30113427, 37742832, 31921190) -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 15, 2022The ATM c.170G>A; p.Trp57Ter variant (rs587779818) is frequently identified in the literature in individuals affected with ataxia-telangiectasia syndrome and various hereditary cancers (Selected references: Li 2000, Goldgar 2011, Susswein 2016, Schon 2019, Skaro 2019, and ClinVar Variation ID: 127341). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES: Goldgar et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011 Jul 25;13(4):R73. PMID: 21787400. Li A et al. Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am J Med Genet. 2000 May 29;92(3):170-7. PMID: 10817650. Schon K et al. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol. 2019 Feb;85(2):170-180. PMID: 30549301. Skaro et al. Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms. Gastroenterology. 2019 May;156(6):1905-1913. PMID: 30716324. Susswein et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312. -
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingDivision of Medical Genetics, University of WashingtonNov 22, 2019This variant has not been reported in the gnomAD database. This variant has been reported a number of times in ClinVar. Multiple studies have detected this variant in individuals with breast cancer, colon cancer, and colon polyps (PMID: 21787400, 27083775, 26681312, 24512911). This variant has also been reported in the medical literature in at least two patients with the autosomal recessive condition ataxia telangiectasia. These two individuals had a second pathogenic variant in the ATM gene (PMID: 10817650). Based on this evidence, we consider this variant to be a pathogenic variant. PM2; PM3 -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 29, 2024- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jan 09, 2024This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 17, 2023This variant changes 1 nucleotide in exon 3 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast, pancreatic, colon cancer, schwannoma and sessile serrated polyposis (PMID: 21787400, 22585167, 24512911, 26681312, 27083775) and in two ataxia telangiectasia families with compound heterozygous mutations in ATM (PMID: 10817650). 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 submitterclinical testingAmbry GeneticsNov 05, 2024The p.W57* pathogenic mutation (also known as c.170G>A), located in coding exon 2 of the ATM gene, results from a G to A substitution at nucleotide position 170. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This alteration has been reported in conjunction with a second pathogenic mutation in two individuals with ataxia telangiectasia (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7), as well as in families with strong histories of cancer of the breast, pancreas, and colon (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Roberts NJ et al. Cancer Discov. 2012 Jan;2:41-6; Gala MK et al. Gastroenterology. 2014 Feb;146:520-9; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Seifert BA et al. Clin. Cancer Res. 2016 Aug;22:4087-94; Bunnell AE et al. J. Genet. Couns. 2017 Feb;26:105-112; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Skaro M et al. Gastroenterology, 2019 05;156:1905-1913). 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;C3469522:Breast cancer, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 12, 2018The c.170G>A (p.Trp57*) variant in the ATM gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated families affected with breast cancer, prostate cancer or pancreatic cancer (PMID 21787400, 22585167, 27083775, 27276934). This variant was also reported in homozygous state in two families affected with ataxia-telangiectasia (PMID 10817650). This variant has never been reported in general population databases. Mono-allelic variants in the ATM gene have been associated with susceptibility to breast cancer (OMIM 114480) whereas bi-allelic variants in this gene are associated with Ataxia-telangiectasia (OMIM 208900). Therefore, this c.170G>A (p.Trp57*) variant in the ATM gene is classified as pathogenic. -
Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Pathogenic and reported on 05-15-2017 by 61756. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
39
DANN
Uncertain
0.99
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.83, 0.86, 0.82, 0.88
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

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

Other links and lift over

dbSNP: rs587779818; hg19: chr11-108098600; API