rs377349459

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000051.4(ATM):c.7913G>A(p.Trp2638Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000744 in 1,612,586 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATM
NM_000051.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.73

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-108332886-G-A is Pathogenic according to our data. Variant chr11-108332886-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7913G>A	p.Trp2638Ter	stop_gained	53/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.7913G>A	p.Trp2638Ter	stop_gained	53/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000479

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250378

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460434

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726620

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

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:

0.000479

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Trp2638*) 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 (rs377349459, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia, colon cancer, and/or prostate cancer (PMID: 9711876, 12815592, 15039971, 21965147, 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 141233). 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The ATM c.7913G>A (p.Trp2638X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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 (e.g. c.8264_8268delATAAG, p.Tyr2755fsX12; c.8266A>T, p.Lys2756X; c.8287C>T, p.Arg2763X; c.8977C>T, p.Arg2993X). The variant of interest has been found in ExAC in 1/120514 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was reported in several patients with Ataxia Telangiectasia (A-T) in homozygous state as well as in compound heterozygous state with other pathogenic/ likely pathogenic variants (Sasaki_Hum Mutat_1998, Coutinho_AmJMedGenet_2004, Demuth_Neurogenetics_2011, Nakamura_Mol Genet Genomic Med_2014). Protein expression and ATM-dependent kinase activity assays from patient cells carrying this variant in heterozygous state and compound heterozygous state with another truncating variant are consistent with the predicted outcome (Fernet_BrJC_2004, Nakamura_Mol Genet Genomic Med_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 11, 2021	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2020	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 11, 2020	This nonsense variant causes the premature termination of ATM protein synthesis. The frequency of this variant in the general population, 0.00016 (4/24942 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 31871109 (2019), 28008555 (2017), prostate cancer (PMID: 27433846 (2016), 28008555 (2017)), and colon cancer (PMID: 26681312 (2015)). The variant has been detected in individuals with ataxia-telangiectasia. Those individuals were compound heterozygous for the variant and an ATM pathogenic or likely pathogenic variant (PMID: 9711876 (1998), 15039971 (2004), 21965147 (2011)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	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 ATM-related cancers (Pritchard 2016, Adedokun 2020); This variant is associated with the following publications: (PMID: 25525159, 23774824, 9711876, 28008555, 27433846, 26681312, 24681528, 28301456, 16953663, 28152038, 25614872, 23807571, 12815592, 15039971, 31871109, 30370249, 21965147, 32832836) -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2021	The p.W2638* pathogenic mutation (also known as c.7913G>A), located in coding exon 52 of the ATM gene, results from a G to A substitution at nucleotide position 7913. This changes the amino acid from a tryptophan to a stop codon within coding exon 52. This mutation has been reported in a compound heterozygous or homozygous state in multiple individuals with classic ataxia-telangiectasia (Sasaki T et al. Hum. Mutat. 1998;12:186-95; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Coutinho G et al. Am. J. Med. Genet. A. 2004 Apr;126A:33-40; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82) and has been identified in breast and prostate cancer cohorts (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). 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	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This variant changes 1 nucleotide in exon 53 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 observed in individuals affected with breast cancer, prostate cancer, colorectal cancer, melanoma (PMID: 26681312, 27433846, 28008555, 31871109, 35353237; DOI: 10.21203/rs.3.rs-1065243/v1), and in homozygous and compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 9711876, 12815592, 15039971, 21965147). Haplotype analyses suggest this variant may be a founder mutation in individuals of African ancestry (PMID: 12815592, 15039971). This variant has been identified in 5/281730 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	curation	Sema4, Sema4	Apr 30, 2021	- -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 01, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 23, 2021

ATM NM_000051 exon 53 p.Trp2638* (c.7913G>A): This variant has been identified as homozygous or compound heterozygous in at least 6 individuals with ataxia telangiectasia (Sasaki 1998 PMID:9711876, Mitui 2003 PMID:12815592, Coutinho 2004 PMID:15039971, Demuth 2011 PMID:21965147). This variant was also identified in at least 2 individuals with colon or prostate cancer (Pritchard 2016 PMID:27433846, Susswein 2016 PMID:26681312). This variant is present in 4/24010 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs377349459). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:141233). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Huang 2013 PMID:23807571) . In summary, this variant is classified as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 25, 2019

ACMG classification criteria: PVS1, PS4, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.62

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

D;A;A

Vest4

0.97

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)

0.090

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