11-108272729-C-G

Variant names:

• chr11-108272729-C-G
• rs1800057
• NM_000051.4:c.3161C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1054T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (30 hom., cov: 32)
  • Exomes 𝑓: 0.023 (462 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 6.36
• Publications: 147 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 42 uncertain in NM_000051.4
• 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 Benign/Likely_benign. ClinVar VariationId is 132695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.3161C>G	p.Pro1054Arg	missense_variant	Exon 22 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3161C>G	p.Pro1054Arg	missense_variant	Exon 22 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2521 AN: 152140 Hom.: 30 Cov.: 32

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

GnomAD2 exomes AF: 0.0166 AC: 4160 AN: 251228 AF XY: 0.0169

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 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.: 32 AF XY: 0.0224 AC XY: 16284 AN XY: 727028

African (AFR) AF: 0.00370 AC: 124 AN: 33480

American (AMR) AF: 0.0115 AC: 516 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 517 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00550 AC: 474 AN: 86254

European-Finnish (FIN) AF: 0.00787 AC: 420 AN: 53354

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5766

European-Non Finnish (NFE) AF: 0.0266 AC: 29607 AN: 1111676

Other (OTH) AF: 0.0199 AC: 1199 AN: 60388

GnomAD4 genome AF: 0.0165 AC: 2517 AN: 152258 Hom.: 30 Cov.: 32 AF XY: 0.0152 AC XY: 1134 AN XY: 74440

African (AFR) AF: 0.00409 AC: 170 AN: 41550

American (AMR) AF: 0.0188 AC: 288 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.00782 AC: 83 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1829 AN: 68022

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0218 Hom.: 46

Bravo AF: 0.0171

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00591 AC: 26

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0169 AC: 2046

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0267

EpiControl AF: 0.0280

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:5

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2018

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Jan 25, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 10, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 17, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Familial cancer of breast Benign:2

May 13, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Benign allele”, 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

Apr 19, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;.
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.9	.;M;M
PhyloP100		6.4
PrimateAI	Benign	0.48	T
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	T
GERP RS		5.6
Varity_R		0.47
gMVP		0.66
Mutation Taster		=77/23	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800057; hg19: chr11-108143456; COSMIC: COSV53728348; COSMIC: COSV53728348;