rs786203606

Positions:

chr11-108227626-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The ATM c.2T>C (p.M1?) variant impacts the initiation codon and is not expected to produce a fully functional protein (PVS1). This variant has been observed in a compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 22146522, 3054930, 12552559, PM3_VeryStrong). This alteration has an allele frequency below 0.001% in the European (non-Finnish) subpopulation in GnomAD (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA197209/MONDO:0016419/020

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ATM
NM_000051.4 start_lost

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 7.17

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:

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.

PM2

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 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

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:

0.00000398

AC:

AN:

251392

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135870

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461386

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727046

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	GeneReviews	Oct 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is present in population databases (rs786203606, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835, 9463314, 12552559, 21792198, 22649200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 187275). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects ATM function (PMID: 21593342, 21792198, 22146522). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 26, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 19, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is expected to interfere with initiation of protein synthesis. In multiple individuals affected with ataxia-telangiectasia (A-T), this variant has been seen with another recessive pathogenic variant in the same gene. At least one other variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies demonstrate either low levels of ATM protein (PMID:22146522, 21459046, 22649200) or no ATM protein (PMID:9463314) with no kinase activity. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Initiation codon variant 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 the heterozygous state in individuals with breast, prostate, and other cancers (Crawford et al., 2017; Decker et al., 2017; Gardner et al., 2018; Waszak et al., 2018; Zafeiriou et al., 2019); Published functional studies demonstrate the possible use of a downstream initiation codon, resulting in trace levels of a truncated protein with no kinase activity, while other studies have shown completely absent protein production (Stankovic et al., 1998; Exley et al., 2011; Reiman et al., 2011; Byrd et al., 2012; Carney et al., 2012); This variant is associated with the following publications: (PMID: 26898890, 28281021, 22649200, 18174244, 28779002, 8845835, 21681852, 22146522, 21593342, 21792198, 9463314, 12552559, 29753700, 30340782, 29308099, 30549301, 30322717, 29922827, 26896183, 21459046) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This variant results in the loss of the translation start codon (methionine at codon 1) of the ATM gene. This variant is expected to disrupt the expression of the full-length ATM protein. The next in-frame methionine occurs at codon 94, but it has not been shown if a functional ATM protein product can be produced using p.Met94 as an alternative translation start site. This variant has been reported in over ten individuals affected with ataxia-telangiectasia in compound heterozygous state with pathogenic mutations (PMID: 8845835, 9463314, 12552559, 15928302, 21593342, 21792198, 22146522, 22649200, 30549301). In cell lines derived from these individuals, a very low level of expression of a truncated ATM protein was observed, probably due to the use of an alternate downstream methionine (PMID: 21593342, 21792198, 22146522). There was no detectable kinase activity in these cell lines. This variant has also been observed in individuals affected with breast cancer (PMID: 28779002, 29308099), ovarian cancer (PMID: 28281021) and brain cancer (PMID: 29753700). This variant has been identified in 1/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2024	The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the ATM gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in individuals with ovarian cancer (Crawford B et al. Breast Cancer Res. Treat., 2017 Jun;163:383-390; Carter NJ et al. Gynecol. Oncol., 2018 12;151(3):481-488), in an individual with medulloblastoma (Waszak SM et al. Lancet Oncol., 2018 06;19(6):785-798), and in an individual with prostate cancer (Zafeiriou Z et al. Eur. Urol., 2019 01;75(1):184-192). This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B at al. J. Med. Genet., 2017 11;54(11):732-741). This alteration has also been reported in a compound heterozygous state in multiple patients with ataxia telangiectasia (Gilad S et al. Hum. Mol. Genet., 1996 Apr;5:433-9; Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62(2):334-45; Buzin CH et al. Hum. Mutat., 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer, 2011 Aug;105(4):586-91; Byrd PJ et al. Br. J. Cancer, 2012 Jan;106:262-8; Schon et al. Ann. Neurol., 2019 02;85(2):170-180; Byrd et al. Nature 2023 Jul;619(7971):828-836). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 16, 2022	The ATM c.2T>C (p.M1?) variant impacts the initiation codon and is not expected to produce a fully functional protein (PVS1). This variant has been observed in a compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 22146522, 3054930, 12552559, PM3_VeryStrong). This alteration has an allele frequency below 0.001% in the European (non-Finnish) subpopulation in GnomAD (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 10, 2024	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 9463314, 21792198, 12552559, 22649200, 22146522, 30549301]. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Pathogenic and reported on 04-23-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;T;T;T;.;T;T;T;T;T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D;D;.;.;.;.;.;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.80

MutationTaster

Benign

1.0

D;D

PROVEAN

Uncertain

-3.0

D;N;D;D;.;N;.;.;.;.;.

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D;D;D;.;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;.;.;.;D;D

Polyphen

0.87, 0.96

.;P;.;.;.;P;P;P;P;P;.

Vest4

0.95, 0.91, 0.96, 0.96

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);

MVP

0.88

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.55

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