chr11-108304801-C-T

Position:

chr11-108304801-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.5623C>T(p.Arg1875*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,398 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ATM
NM_000051.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.45

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 11-108304801-C-T is Pathogenic according to our data. Variant chr11-108304801-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 245815.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
ATM	NM_000051.4 linkuse as main transcript	c.5623C>T	p.Arg1875*	stop_gained	37/63	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.5623C>T	p.Arg1875*	stop_gained	37/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249754

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135130

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:

0.00

Gnomad FIN exome

AF:

0.0000475

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461318

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000481

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 08, 2024	The p.R1875* pathogenic mutation (also known as c.5623C>T), located in coding exon 36 of the ATM gene, results from a C to T substitution at nucleotide position 5623. This changes the amino acid from an arginine to a stop codon within coding exon 36. This mutation has been reported in both the homozygous and compound heterozygous state in multiple patients with ataxia-telangiectasia (A-T) (Becker-Catania SG et al. Mol Genet Metab, 2000 Jun;70:122-33; Cummins G et al. Parkinsonism Relat Disord, 2013 Dec;19:1173-4; Sheikhbahaei S et al. Allergy Asthma Clin Immunol. 2016 Dec 2;12:62). One study, in an A-T patient who was positive for this mutation along with another truncation ATM alteration, demonstrated residual ATM protein expression and activity was reportedly absent (Carney EF et al. J. Immunol. 2012 Jul; 189(1):261-8). This mutation has been detected in patients with multiple cancer types including breast, ovarian, pancreatic, prostate and melanoma (Tavtigian SV et al. Am J Hum Genet, 2009 Oct;85:427-46; Decker B et al. J Med Genet, 2017 11;54:732-741; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Cremin C et al. Cancer Med, 2020 06;9:4004-4013; Feliubadaló L et al. Clin Chem, 2021 03;67:518-533; Dorling et al. N Engl J Med. 2021 02;384:428-439; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). Furthermore, tumor studies have revealed loss of heterozygosity (LOH) associated with this mutation (Goldgar DE et al. Breast Cancer Res. 2011; 13(4):R73). 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.5623C>T (p.Arg1875*) 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 0.0013%, (3/235,362 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0020%, (2/102100 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This variant has been reported in at least three ataxia-telangiectasia probands together with (likely) pathogenic variants (PMID: 21792198, 22649200, 21778326) and in two homozygous probands (PMID: 10873394, 9450906), which awards it with at least 2 points as per ClinGen SVI Recommendation for in trans Criterion (PM3_Strong; PMID: 21965147). Assays performed with lymphoblastoid cell lines of an homozygous and a compound heterozygous ataxia-telangiectasia patients showed reduced levels (PMID: 10873394) and absence (PMID: 21778326) of ATM protein, respectively. Additionally, very little phosphorylation of SMC1, KAP1, and CHK2 proteins was observed in the latter patient (PS3_Moderate, PMID: 21778326). c.1463G>A 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_Strong + PS3_Moderate (PMID: 33280026) -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 14, 2021	- -
Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 05, 2023	This variant changes 1 nucleotide in exon 37 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 cancer (PMID: 19781682, 21787400, 26976419, 28779002, 33471991), pancreatic cancer (PMID: 32255556), and in homozygous and compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 9450906, 10873394, 21792198, 21792198, 30549301). This variant has been identified in 5/249754 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. -

Ataxia-telangiectasia syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2021	Variant summary: ATM c.5623C>T (p.Arg1875X) 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. The variant allele was found at a frequency of 2e-05 in 249754 control chromosomes. c.5623C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (example, Gilad_1998, Becker-Catnia_2000, Reiman_2011, Sheikhbahaei_2016). These data indicate that the variant is very likely to be associated with disease. Nine 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Arg1875*) 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 (rs376603775, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9450906, 10873394, 21792198, 26976419, 27980538). ClinVar contains an entry for this variant (Variation ID: 245815). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Familial cancer of breast

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Nov 14, 2019	This variant creates a premature stop codon. The variant transcript is predicted to be degraded by nonsense-mediated decay or lead to a truncated protein. Loss of expression of one allele of ATM is a well-established mechanism of disease (Huang2013, Podralska 2014). This variant has been reported in the literature in an individual with breast cancer (Tung 2016) and in individuals with ataxia-telangiectasia (Gilad 1998, Becker-Catania 2000, Reiman 2011). This variant has an allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 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	Baylor Genetics	Feb 18, 2024	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Feb 25, 2019

The c.5623C>T (p.Arg1875*) variant in exon 37 of the ATM gene introduces a premature termination codon and is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been observed in at least two individuals with ataxia telangiectasia (PMID 9450906, 22649200) and multiple individuals with breast cancer (PMID 19781682, 20346647, 21787400,26976419). This variant is extremely rare in a heterozygous state in a large population database (gnomAD). Therefore, the c.5623C>T (p.Arg1875*) variant in the ATM gene is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 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; Observed in individuals with ataxia-telangiectasia in the apparent homozygous and compound heterozygous states, and cell lines from some of these patients displayed impaired phosphorylation and DNA damage response, and reduced ATM protein expression (Gilad et al., 1998; Becker-Catania 2000; Keimling et al., 2011); Observed in individuals with ATM-related cancers (Hollestelle et al., 2010; Tung et al., 2016; Decker et al., 2017; Whitworth et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26976419, 35047863, 10330348, 21787400, 24008619, 20346647, 27980538, 28779002, 29909963, 30549301, 9450906, 30322717, 32255556, 29625052, 34426522, 25525159, 33436325, 29922827, 33804961, 26896183, 28888541, 10873394, 21778326) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.86

Vest4

0.88

GERP RS

4.4

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