11-108289623-C-T

Position:

chr11-108289623-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):c.4258C>T(p.Leu1420Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,605,174 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 249 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25O:1

Conservation

PhyloP100: 0.809

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0078905225).

BP6

Variant 11-108289623-C-T is Benign according to our data. Variant chr11-108289623-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108289623-C-T is described in Lovd as [Benign]. Variant chr11-108289623-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1720/152268) while in subpopulation NFE AF= 0.0186 (1266/67990). AF 95% confidence interval is 0.0178. There are 16 homozygotes in gnomad4. There are 792 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4258C>T	p.Leu1420Phe	missense_variant	29/63	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.4258C>T	p.Leu1420Phe	missense_variant	29/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1720

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.00933

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.0110

AC:

2715

AN:

245854

Hom.:

AF XY:

0.0114

AC XY:

1516

AN XY:

133066

show subpopulations

Gnomad AFR exome

AF:

0.00291

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00154

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00625

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.00992

GnomAD4 exome

AF:

0.0167

AC:

24336

AN:

1452906

Hom.:

249

Cov.:

AF XY:

0.0165

AC XY:

11933

AN XY:

721996

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.00399

Gnomad4 ASJ exome

AF:

0.00155

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00768

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0113

AC:

1720

AN:

152268

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

792

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00346

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00891

Gnomad4 FIN

AF:

0.00933

Gnomad4 NFE

AF:

0.0186

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0157

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00364

AC:

ESP6500EA

AF:

0.0178

AC:

153

ExAC

AF:

0.0120

AC:

1461

Asia WGS

AF:

0.00202

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:25Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Hereditary cancer-predisposing syndrome

Benign:5

Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 05, 2022	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, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 03, 2016	- -

Ataxia-telangiectasia syndrome

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 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

May 07, 2019

- -

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.Leu1420Phe variant was identified in 81 of 4298 proband chromosomes (frequency: 0.02) from English, French, Dutch, American Indian/Non-Indian, Australian and North American individuals or families with familial and primary breast cancers, AT disease, CML, and individuals undergoing radiation therapy and was present in 108 of 6302 control chromosomes (frequency: 0.02) from healthy individuals (Johnson 2007 , LaPaglia 2010, Broeks 2008, Melo 2001, Petereit 2013, Renwick 2006, Li 2000, Thompson 2005, ). In 2 population-based, case-control studies, the variant was found not to increase breast cancer risk (Einarsdottir 2006, Thompson 2005). The variant was also identified in dbSNP (ID: rs1800058) as â€šÃ„Ãºotherâ€šÃ„Ã¹, ClinVar (classified as conflicting interpretations of pathogenicity: classified benign by GeneDx, Div of Genomic Diagnostics, Children's Hospital of Philadelphia, Vantari Genetics, Prevention Genetics, Emory Genetics, Color Genomics Inc., Invitae; likely benign by Genetic Services Laboratory, U of Chicago; uncertain significance by Ambry Genetics; and unclassified by ITMI), Clinvitae (5X), LOVD 3.0 (2X), ATM-LOVD (1x). The variant was not identified in GeneInsight-COGR, Cosmic and MutDB. The variant was identified in control databases in 3069 (22 homozygous) of 272226 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 2316 of 124884 chromosomes (freq: 0.019), European (Finnish) in 279 of 25640 chromosomes (freq: 0.011), Other in 67 of 6316 chromosomes (freq: 0.011). The p.Leu1420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. -

Familial cancer of breast

Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 17, 2024

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

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

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.83

T;.;T

MetaRNN

Benign

0.0079

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Benign

0.15

Sift

Benign

0.071

T;T;D

Sift4G

Benign

0.061

T;T;D

Polyphen

0.15

B;B;.

Vest4

0.22

MPC

0.17

ClinPred

0.020

GERP RS

-0.47

Varity_R

0.089

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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