rs587779818

Variant names:

• chr11-108227873-G-A
• rs587779818
• NM_000051.4:c.170G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108227873-G-A
• chr11-108227873-G-C
• chr11-108227873-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 8.59

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 11-108227873-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 rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.170G>A	p.Trp57*	stop_gained	Exon 3 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.170G>A	p.Trp57*	stop_gained	Exon 3 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151962 Hom.: 0 Cov.: 33

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

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

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:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jun 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.170G>A (p.Trp57*) variant causes the premature termination of ATM protein synthesis. This variant has been reported in the published literature in individuals affected with ataxia-telangiectasia (AT) in a compound heterozygous state co-occurring with another ATM variant (PMID: 10817650 (2000), 30549301 (2019), 31921190 (2019)). This variant is also reported in individuals affected with breast cancer (PMID: 21787400 (2011), 27153395 (2016), 27276934 (2016)), pancreatic cancer (PMID: 22585167 (2012), 27083775 (2016), 28767289 (2017), 30716324 (2019)), and colon/rectal cancer (PMID: 26681312 (2015), 27978560 (2016)). The frequency of this variant in the general population, 0.0000066 (1/151962 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Feb 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; 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) -

Apr 15, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

May 21, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2017

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM3:Very Strong, PVS1, PM2 -

Ataxia-telangiectasia syndrome Pathogenic:5

Jun 29, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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. -

Nov 01, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:3

Feb 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Nov 22, 2019

Division of Medical Genetics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

Feb 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

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

Apr 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 12, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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

Other links and lift over

dbSNP: rs587779818; hg19: chr11-108098600;