11-108295002-C-T

Position:

chr11-108295002-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_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 (★★). 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 1.90

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 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 id is 187207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108295002-C-T is described in Lovd as [Pathogenic]. Variant chr11-108295002-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4852C>T	p.Arg1618*	stop_gained	32/63	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.4852C>T	p.Arg1618*	stop_gained	32/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251340

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135830

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

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:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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 (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
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: <0.001%). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2018	- -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 24, 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	Centogene AG - the Rare Disease Company	Feb 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 12, 2024	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 32 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	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

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2024

- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2022

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.85

Vest4

0.94

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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.

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