11-108295002-C-T

Variant names:

• chr11-108295002-C-T
• rs762083530
• NM_000051.4:c.4852C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000051.4(ATM):​c.4852C>T​(p.Arg1618*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,780 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1618R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 1.90
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108295002-C-T is Pathogenic according to our data. Variant chr11-108295002-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 187207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.4852C>T	p.Arg1618*	stop_gained	Exon 32 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4852C>T	p.Arg1618*	stop_gained	Exon 33 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.4852C>T	p.Arg1618*	stop_gained	Exon 32 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.4852C>T	p.Arg1618*	stop_gained	Exon 33 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.*51C>T		3_prime_UTR	Exon 30 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251340 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111898

Other (OTH) AF: 0.0000662 AC: 4 AN: 60382

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00000473 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:7

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2024

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.Arg1618*) 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 (rs762083530, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 9872980, 15843990, 19404735). ClinVar contains an entry for this variant (Variation ID: 187207). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.

May 31, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Aug 29, 2019

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.4852C>T (p.Arg1618X) 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 allele was found at a frequency of 4e-06 in 251340 control chromosomes (gnomAD). c.4852C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Babaei_2005, Hacia_1998, Micol_2011) and in at least one individual affected with breast cancer (Paglia_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function using a cell line derived from a patient (who carried the variant of interest and another variant) demonstrated decreased phosphorylation of ATM target proteins, defective cell cycle checkpoint control following exposure to Camptothecin (CPT) and severely decreased ATM protein expression (Fievet_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed stop gained c.4852C>T(p.Arg1618Ter) variant in ATM gene has been reported in compound heterozygous or homozygous state in individuals affected with ataxia-telangiectasia (Hacia JG, et.al., 1998; Babaei M, et. al.,2005). Experimental evidence demonstrated decreased phosphorylation of ATM target proteins, defective cell cycle checkpoint control following exposure to Camptothecin (CPT) and severely decreased ATM protein expression (Fiévet A, et. al., 2019). This variant is present with an allele frequency of 0.0004% in gnomAD Exomes database. This variant has been submitted to ClinVar as pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predict a damaging effect on protein structure and function for this varian. The nucleotide change c.4852C>T in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Podralska MJ, et. al., 2014). For these reasons, this variant has been classified as Pathogenic.

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). 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: VCV000187207 / PMID: 9872980). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

May 07, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Pathogenic:4

Apr 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 24, 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.

Jan 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 12, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:3

Jul 25, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1618* pathogenic mutation (also known as c.4852C>T) located in coding exon 31 of the ATM gene, results from a C to T substitution at nucleotide position 4852. This changes the amino acid from an arginine to a stop codon within coding exon 31. This alteration has been described in multiple individuals with ataxia-telangiectasia (Hacia JG et al. Genome Res. 1998 Dec;8(12):1245-58; Babaei M et al. Hum. Genet. 2005 Jul;117:101-6; Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). This alteration has also been reported in individuals with breast, colorectal, pancreatic and prostate cancers (Paglia LL et al. Breast Cancer Res Treat, 2010 Jan;119:443-52; Hampel H et al. JAMA Oncol, 2018 06;4:806-813; Kondo T et al. Oncotarget, 2018 Apr;9:19817-19825; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). 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.

Dec 11, 2024

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 32/63 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An in vitro study showed that this variant disrupted cellular function (PMID: 31050087). This variant has been reported in individuals affected with breast cancer (PMID: 19404735), pancreatic cancer (PMID: 29731985), and ataxia-telangiectasia (PMID: 9872980, 15843990, 21665257). This variant has been identified in 1/251340 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.

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4852C>T (p.Arg1618*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It appears only once in the gnomAD v2.1.1 non-cancer dataset, specifically in the South Asian subpopulation (PM2; http://gnomad.broadinstitute.org). ). This variant has been reported in three ataxia-telangiectasia probands in homozygosis or heterozygosis (PS4_Moderate; PMID: 9872980, 15843990). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS4_Moderate (PMID: 33280026).

Abnormal central motor function Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:1

Jun 30, 2022

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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ATM-related cancers (Paglia et al., 2010; Kondo et al., 2018); This variant is associated with the following publications: (PMID: 9872980, 25525159, 29731985, 31118792, 33436325, 32338768, 32853339, 33280026, 35428255, 33842585, 29922827, 15843990, 19404735)

ATM-related disorder Pathogenic:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.4852C>T variant is predicted to result in premature protein termination (p.Arg1618*). This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with autosomal recessive ataxia telangiectasia (Hacia et al. 1998. PubMed ID: 9872980; Babaei et al. 2005. PubMed ID: 15843990; Micol et al. 2011. PubMed ID: 21665257, Table E1). It has also been reported in an individual with breast cancer and a family history of breast and hematological malignancy (Paglia et al. 2010. PubMed ID: 19404735), and as a somatic change in a colorectal tumor specimen (Hampel et al. 2018. PubMed ID: 29596542, eWorksheet). This variant is reported in 1 of ~251,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187207/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		1.9
Vest4		0.94
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs762083530; hg19: chr11-108165729; COSMIC: COSV53726137; COSMIC: COSV53726137;