11-108272729-C-G

Position:

chr11-108272729-C-G

Variant summary

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

The NM_000051.4(ATM):c.3161C>G(p.Pro1054Arg) variant causes a missense change. The variant allele was found at a frequency of 0.022 in 1,613,692 control chromosomes in the GnomAD database, including 492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 30 hom., cov: 32)

Exomes 𝑓: 0.023 ( 462 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 6.36

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074827075).

BP6

Variant 11-108272729-C-G is Benign according to our data. Variant chr11-108272729-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 132695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108272729-C-G is described in Lovd as [Benign]. Variant chr11-108272729-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2517/152258) while in subpopulation NFE AF= 0.0269 (1829/68022). AF 95% confidence interval is 0.0259. There are 30 homozygotes in gnomad4. There are 1134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.3161C>G	p.Pro1054Arg	missense_variant	22/63	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.3161C>G	p.Pro1054Arg	missense_variant	22/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2521

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0269

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0166

AC:

4160

AN:

251228

Hom.:

AF XY:

0.0169

AC XY:

2302

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00425

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00503

Gnomad FIN exome

AF:

0.00801

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0226

AC:

33044

AN:

1461434

Hom.:

462

Cov.:

AF XY:

0.0224

AC XY:

16284

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.0115

Gnomad4 ASJ exome

AF:

0.0198

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00550

Gnomad4 FIN exome

AF:

0.00787

Gnomad4 NFE exome

AF:

0.0266

Gnomad4 OTH exome

AF:

0.0199

GnomAD4 genome

AF:

0.0165

AC:

2517

AN:

152258

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1134

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00782

Gnomad4 NFE

AF:

0.0269

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.0218

Hom.:

Bravo

AF:

0.0171

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00591

AC:

ESP6500EA

AF:

0.0228

AC:

196

ExAC

AF:

0.0169

AC:

2046

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0267

EpiControl

AF:

0.0280

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 19, 2018	- -
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	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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. -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2020	- -

not specified

Benign:3Other:1

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	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30957677, 31382929, 26122175, 18502988, 24728327, 27599564, 27153395, 10464642, 17502119, 22529920, 21833744, 19431188, 23585524, 15101044, 11996792, 20826828, 23125224) -
Likely 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	Nov 17, 2023	- -

Familial cancer of breast

Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 13, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Pro1054Arg variant was identified in both proband chromosomes (frequency not specified) from Swiss, Brazilian and European individuals or families with (early onset or sporadic) breast cancers, and in control chromosomes (frequency not specified) from healthy individuals (Mangone 2015, Milne 2009, Maillet 2002), increasing the likelihood this variant is not associated with breast cancer. Genotyping of 5 polymorphisms (with MAF 0.9-2.6%) including this variant in a large case control study, showed that the 5 missense polymorphisms were associated with a small increased risk of breast cancer (Fletecher 2010). The variant was confirmed to be associated with an increased risk of prostate cancer in a cohort of prostate cancer cases, being identified in 50 of 522 proband chromosomes (frequency 0.096), and 22 of 920 healthy controls were found to be carriers (1 homozygous, frequency: 0.024, Meyer 2007). The variant was identified in dbSNP (ID: rs1800057) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, Clinvitae database (classified as benign), ClinVar database (classification benign by Ambry Genetics, Emory Genetics, Color Genomics Inc, Prevention Genetics, Invitae and not classified by ITMI), and in COSMIC (in a squamous cell carcinoma, and lymphoid neoplasm-Burkitt lymphoma). The variant was also identified in LOVD 3.0 (2x) databases, but not in the ATM-LOVD database. The variant was identified in control databases in 4511 of 277018 chromosomes at a frequency of 0.016284 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%: European (Non-Finnish) in 3306 of 126596 chromosomes (freq: 0.026), Ashkenazi Jewish in 224 of 10148 chromosomes (freq: 0.022), Other in 122 of 6458 chromosomes (freq: 0.019), Latino in 390 of 34412 chromosomes (freq: 0.011). The p.Pro1054 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs 8 nucleotides from the intron-exon junction and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

Likely 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

Uncertain

0.51

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

D;D;.

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.9

.;M;M

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.95, 0.92

MPC

0.59

ClinPred

0.022

GERP RS

5.6

Varity_R

0.47

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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