chr11-108267318-C-T

Position:

chr11-108267318-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP2_StrongBP4BA1

This summary comes from the ClinGen Evidence Repository: The ATM c.2614C>T (p.Pro872Ser) variant has a GnomAD FAF 4.6% (AFR) exceeding ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous or compound heterozygous state (presumed and/or confirmed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, Clinical Diagnostic Laboratories). This variant is predicted tolerated by multiple protein in silico tools (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157083/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.013 ( 53 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 39 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:29O:1

Conservation

PhyloP100: 1.04

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:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP2

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

BP4

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

BA1

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.2614C>T	p.Pro872Ser	missense_variant	17/63	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.2614C>T	p.Pro872Ser	missense_variant	17/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1946

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00960

GnomAD3 exomes

AF:

0.00353

AC:

888

AN:

251426

Hom.:

AF XY:

0.00251

AC XY:

341

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0478

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00133

AC:

1943

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

861

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0450

Gnomad4 AMR exome

AF:

0.00268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.00290

GnomAD4 genome

AF:

0.0128

AC:

1953

AN:

152126

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

873

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0438

Gnomad4 AMR

AF:

0.00648

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00950

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.0152

ESP6500AA

AF:

0.0470

AC:

207

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00463

AC:

562

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:29Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:6

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ATM: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 18, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -

Ataxia-telangiectasia syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial cancer of breast

Benign:3

Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.2614C>T (p.Pro872Ser) variant has a GnomAD FAF 4.6% (AFR) exceeding ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous or compound heterozygous state (presumed and/or confirmed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, Clinical Diagnostic Laboratories). This variant is predicted tolerated by multiple protein in silico tools (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 09, 2024	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 02, 2021

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 22, 2022

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Pro872Ser variant was identified in 10 of 1192 proband chromosomes (frequency: 0.008) from individuals or families with breast cancer, multiple myeloma and from breast cancer tumors and was not identified in 200 control chromosomes from healthy individuals (Austen 2008, Rodriguez 2002, Bretsky 2003). The variant was also identified in the following databases: dbSNP (ID: rs3218673) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, in ClinVar (classified as 5x benign and 1x likely benign), Clinvitae (classified as 5x benign and 1x conflicting interpretations of pathogenicity), and Cosmic (1x as neutral). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1212 of 277156 (32 homozygous) chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1102 of 24020 chromosomes (freq: 0.046). The p.Pro872Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.8

DANN

Benign

0.56

DEOGEN2

Benign

0.048

.;T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.69

T;T;.

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

.;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.55

N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.052, 0.072

MVP

0.64

MPC

0.12

ClinPred

0.0034

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.11

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