chr11-108365476-C-T

Position:

chr11-108365476-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS3_SupportingPM3PVS1

This summary comes from the ClinGen Evidence Repository: The ATM c.9139C>T (p.Arg3047Ter) variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is above the PM2 threshold of 0.001% but below the BS1 threshold of 0.05%. This variant is expected to produce an NMD-escaping transcript that adversely affects the critical FATKIN domain (PVS1). This variant has been observed in a compound heterozygous state (confirmed) in multiple individuals with ataxia-telangiectasia (PMIDs: 10980530, 26628246, 19691550, 22649200, PM3_verystrong). This variant is non-functional in a single ATM-specific protein assay (PMID:19431188, PS3_supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115937/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATM
NM_000051.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 3.04

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:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.9139C>T	p.Arg3047*	stop_gained	63/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.9139C>T	p.Arg3047*	stop_gained	63/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251438

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135898

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:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727236

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:

0.0000927

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	Based on in-silico analysis tools(CADD - 39, GREP++ - 5.090), this variant c.9139C>T is predicted to introduce a premature termination codon which is likely to result in either truncated protein or might undergo nonsense-mediated mRNA decay(MutationTaster). ACMG criteria: PVS1, PM2, PM3, PS3, PP5 - Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	This sequence change creates a premature translational stop signal (p.Arg3047*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the ATM protein. This variant is present in population databases (rs121434219, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 8755918, 10980530, 18560558, 19691550, 26628246). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3029). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 19431188). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2021	Variant summary: ATM c.9139C>T (p.Arg3047X) located in the last exon, 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 not been classified as pathogenic by our laboratory but have been reported in the HGMD database. The variant allele was found at a frequency of 1.6e-05 in 251438 control chromosomes (gnomAD). c.9139C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (examples: Toyoshima_1998, Stankovic_1998, Delia_2000, Laake_2000, Carney_2012, Liu_2016, Schon_2019). These data indicate that the variant is associated with disease. One publication reports experimental evidence evaluating an impact on protein. Reduced protein levels <10% was observed from a patient homozygous for this variant (Delia_2000). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 18, 2022	The ATM c.9139C>T (p.Arg3047Ter) variant has a GnomAD (v2.1.1) allele frequency of 0.001768% which is above the PM2 threshold of 0.001% but below the BS1 threshold of 0.05%. This variant is expected to produce an NMD-escaping transcript that adversely affects the critical FATKIN domain (PVS1). This variant has been observed in a compound heterozygous state (confirmed) in multiple individuals with ataxia-telangiectasia (PMIDs: 10980530, 26628246, 19691550, 22649200, PM3_verystrong). This variant is non-functional in a single ATM-specific protein assay (PMID: 19431188, PS3_supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 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	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 28, 2022	The ATM c.9139C>T (p.Arg3047Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. A functional assay showed that this variant has no detectable kinase activity (PMID: 19431188). This variant has a maximum frequency of 0.0098% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), and is not reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). This variant has been observed in a compound heterozygous state in multiple individuals with ataxia-telangiectasia (PMID: 10980530, 26628246, 19691550, 22649200). In summary, this variant meets criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 21, 2022	The p.R3047* pathogenic mutation (also known as c.9139C>T), located in coding exon 62 of the ATM gene, results from a C to T substitution at nucleotide position 9139. This changes the amino acid from an arginine to a stop codon within coding exon 62. This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 10 amino acids of the protein. However, premature stop codons are typically deleterious in nature and functional studies have indicated that while this pathogenic alteration does not inhibit ATM protein expression, it does result in little to no kinase activity of downstream targets (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Banin S et al. Science. 1998 Sep;281:1674-7; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30; Byrd PJ et al. Br.J. Cancer. 2012 Jan;106:262-8; Carney EF et al. J. Immunol. 2012 Jul;189:261-8). Another functional study showed that this mutant protein could be activated in response to DNA damage but not in response to oxidation (Guo Z et al. Science. 2010 Oct;330:517-21; Guo Z et al. Cell Cycle. 2010 Dec;9:4805-11). This pathogenic mutation has been reported in conjunction with a second ATM mutation in an individual with an atypical ataxia-telangiectasia (A-T) phenotype (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30). It has also been detected in the compound heterozygous state, as well as in the homozygous state, in families diagnosed with A-T (Toyoshima M et al. Am. J. Med. Genet. 1998 Jan;75:141-4; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Chessa L et al. Ann. Hum. Genet. 2009 Sep;73:532-9; Byrd PJ et al. Br.J. Cancer. 2012 Jan;106:262-8; Carney EF et al. J. Immunol. 2012 Jul;189:261-8; Liu XL et al. Neurosci. Lett. 2016 Jan;611:112-5; Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Laake K et al. Hum. Mutat. 2000 Sep;16:232-46). This alteration has also been reported in patients diagnosed with breast and/or pancreatic cancers (Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2018 Jan;16:4; Dudley B et al. Cancer. 2018 Apr;124:1691-1700). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 15, 2021	This variant changes 1 nucleotide in exon 63 of the ATM gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein, it is expected to disrupt the FATC domain. A functional study has shown this variant protein has no detectable kinase activity in an in vitro assay in a transfected ATM-null cell line (PMID: 19431188). This variant has been reported in homozygous carriers (siblings) (PMID: 19691550) and multiple unrelated compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 8755918, 9450874, 10980530, 19691550, 22649200, 26628246). This variant has also been reported in individuals affected with colorectal, pancreatic, gastric and breast cancer (PMID: 28724667, 29360161, 33048355). This variant has been identified in 5/282840 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;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

Malignant tumor of urinary bladder

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2022

Nonsense variant predicted to result in protein truncation, as the last 10 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; 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; Published functional studies demonstrate a damaging effect: absent kinase activity and deficient activation by oxidation (Barone et al., 2009; Guo et al., 2010; van Os et al., 2017); Observed in the homozygous state in at least one individual with ataxia-telangiectasia (A-T) and in trans with ATM pathogenic variants in other affected individuals (Toyoshima et al., 1998; Chessa et al., 2009; Byrd et al., 2012; Liu et al., 2016); This variant is associated with the following publications: (PMID: 10397742, 9497252, 26787654, 17124347, 27153395, 32866655, 29922827, 28888541, 19691550, 22146522, 8755918, 21933854, 26628246, 18560558, 15928302, 11243240, 22649200, 10234507, 22079189, 9450874, 1632451, 19431188, 28126470, 9733514, 28543935, 20966255, 28779002, 29371908, 29360161, 26556299, 28724667, 30549301, 30607632, 26896183, 32427313, 23532176) -

Ataxia-telangiectasia without immunodeficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.90

Vest4

0.68

GERP RS

5.1

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