rs781404312

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000051.4(ATM):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000248 in 1,613,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.11

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 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_000051.4 (ATM) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108227627-G-A is Pathogenic according to our data. Variant chr11-108227627-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108227627-G-A 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.3G>A	p.Met1?	start_lost	2/63	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.3G>A	p.Met1?	start_lost	2/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251388

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000137

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727050

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 20, 2021	This variant disrupts the translation initiation codon of the ATM mRNA and is predicted to interfere with ATM protein synthesis. The frequency of this variant in the general population, 0.000062 (1/16252 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in one individual with pancreatic cancer (PMIDs:28767289 (2017) and 31285527 (2019)), and two individuals with breast cancer (PMID:28779002 (2017)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2023	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in the compound heterozygous state in individuals with ataxia telangiectasia (Buzin et al., 2003); Observed in individuals with breast and pancreatic cancer (Decker et al., 2017; Shindo et al., 2017; Hutchings et al., 2019; Dorling et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28779002, 28767289, 21681852, 29625052, 12552559, 35483985, 33471991, 35047863, 32427313, 31285527, 29922827) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 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. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both ataxia-telangiectasia (A-T) and cancer patients (PMID: 12552559, 28779002, 28767289, 31285527). -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ATM: PM1, PM2, PVS1:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Ataxia-telangiectasia syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2019	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2022	Variant summary: ATM c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met94) is located in the encoded protein. An activation of potential downstream translation initiation site would result in a shortened protein missing the first 93 amino acids from the protein sequence, part of the telomere-length maintenance and DNA damage repair domain (IPR021668). Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251388 control chromosomes (gnomAD). c.3G>A has been reported in the literature in the compound heterozygous state in individuals affected with Ataxia-Telangiectasia (e.g. Buzin_2003). The variant has also been reported in individuals affected with breast cancer, pancreatic cancer, endometrial cancer, and bladder urothelial carcinoma (Decker_2017, Shindo_2017, Huang_2018, Hutchings_2019, Dorling_2021, Yu_2022, Karpel_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Functional studies on other ATM variants affecting the initiation codon (c.1A>G, c.2T>C) have demonstrated the potential of translation initiation from a downstream AUG codon resulting in a truncated protein. The resulting ATM protein was expressed at low levels and lacked ATM kinase activity (PMIDs: 22146522, 21792198). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as either pathogenic (n=7) or likely pathogenic (n=2). 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 13, 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 (rs781404312, gnomAD 0.007%). Disruption of the initiator codon has been observed in individuals with ataxia-telangiectasia (PMID: 8845835, 9463314, 12552559, 21792198, 22649200). ClinVar contains an entry for this variant (Variation ID: 188901). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 25, 2024	The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the ATM gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been detected in conjunction with a second ATM mutation in two patients with ataxia telangiectasia (Buzin CH et al. Hum. Mutat. 2003 Feb; 21(2):123-31). It was also identified in 2/13087 breast cancer cases and 0/5488 control individuals in the UK as well as a familial pancreatic cancer kindred in the US (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). 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 variant is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 28, 2020	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia, breast cancer, and pancreatic cancer (PMID: 12552559, 28767289, 28779002). This variant has been identified in 1/251388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 10, 2024

ACMG categories: PVS1,PM2_sup,PM3 -

Familial cancer of breast

Pathogenic:1

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]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.68

MetaRNN

Uncertain

0.65

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

MetaSVM

Benign

-0.92

PROVEAN

Uncertain

-2.4

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

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.87, 0.69

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

Vest4

0.94, 0.90, 0.96

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);

MVP

0.90

ClinPred

0.98

GERP RS

5.1

Varity_R

0.60

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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