11-108244000-G-C

Variant names:

• chr11-108244000-G-C
• rs3218707
• NM_000051.4:c.544G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.544G>C​(p.Val182Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00194 in 1,610,832 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. V182G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (19 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28 O:1
• Conservation: PhyloP100: 3.86
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032812655).
• BP6: Variant 11-108244000-G-C is Benign according to our data. Variant chr11-108244000-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00706 (1066/151066) while in subpopulation AFR AF = 0.0223 (917/41072). AF 95% confidence interval is 0.0211. There are 12 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.544G>C	p.Val182Leu	missense_variant	Exon 6 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.544G>C	p.Val182Leu	missense_variant	Exon 6 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1065 AN: 150946 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00647

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000195

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.00674

GnomAD2 exomes AF: 0.00252 AC: 626 AN: 248182 AF XY: 0.00201

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00141 AC: 2059 AN: 1459766 Hom.: 19 Cov.: 34 AF XY: 0.00132 AC XY: 955 AN XY: 726094

African (AFR) AF: 0.0251 AC: 839 AN: 33454

American (AMR) AF: 0.00470 AC: 209 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.000384 AC: 10 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86086

European-Finnish (FIN) AF: 0.000394 AC: 21 AN: 53292

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5760

European-Non Finnish (NFE) AF: 0.000662 AC: 735 AN: 1110720

Other (OTH) AF: 0.00299 AC: 180 AN: 60294

GnomAD4 genome AF: 0.00706 AC: 1066 AN: 151066 Hom.: 12 Cov.: 32 AF XY: 0.00674 AC XY: 497 AN XY: 73706

African (AFR) AF: 0.0223 AC: 917 AN: 41072

American (AMR) AF: 0.00647 AC: 98 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.000195 AC: 2 AN: 10264

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67878

Other (OTH) AF: 0.00667 AC: 14 AN: 2100

Alfa AF: 0.00192 Hom.: 2

Bravo AF: 0.00830

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0223 AC: 98

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00293 AC: 356

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:28 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8 Other:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 17, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Oct 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 30, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:6

Mar 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

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

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 15, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4, BS1, BS2

Sep 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ataxia-telangiectasia syndrome Benign:5

Mar 23, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

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.

Sep 27, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 22, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:5

Nov 18, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 16, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 15, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Nov 24, 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.

Feb 04, 2016

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Benign:2

Apr 19, 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

Malignant tumor of breast Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

ATM, EXON6, c.544G>C, p.Val182Leu, Heterozygous, Benign The ATM p.Val182Leu variant was identified in 7 of 856 proband chromosomes (frequency: 0.008) from a multiethnic American cohort of individuals or families with breast cancer and in 4 of 852 control chromosomes (frequency: 0.005) from healthy women (Bretsky 2003). The variant was also identified in dbSNP (ID: rs3218707) as “With other allele” and ClinVar (classified as benign by GeneDx, Ambry Genetics, Invitae, Prevention Genetics, and four other submitters; and as likely benign by Vantari Genetics and True Health Diagnostics). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 814 of 273878 chromosomes at a frequency of 0.003 (Genome Aggregation Database Feb 27, 2017), increasing the likelihood this could be a low frequency benign variant. It was observed in the following populations: African in 526 of 23792 chromosomes (freq: 0.02) (1 homozygote in ExAC), Other in 19 of 6360 chromosomes (freq: 0.003), Latino in 159 of 34126 chromosomes (freq: 0.005), European Non-Finnish in 96 of 124726 chromosomes (freq: 0.0008) (1 homozygote in ExAC), Ashkenazi Jewish in 5 of 10042 chromosomes (freq: 0.0005), European Finnish in 7 of 25552 chromosomes (freq: 0.0003), and South Asian in 2 of 30596 chromosomes (freq: 0.00007); it was not observed in the East Asian population. The variant was identified by our laboratory in 6 individuals with breast, colon or endometrial cancers, co-occurring with multiple pathogenic variants: BRCA2, c.2957_2958insG (p.Asn986Lysfs*2) and CHEK2, c.1100del (p.Thr367Metfs*15). The p.Val182 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Leu variant impacts 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) 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. Assessment Date: 2019/07/03 References (PMIDs): 11821961, 12917204, 17640065

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.0	.;T;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	D;D;T;.
MetaRNN	Benign	0.0033	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;L;.;L
PhyloP100		3.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.063	T;T;D;T
Sift4G	Uncertain	0.053	T;T;T;T
Vest4		0.0
ClinPred		0.0053	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.11
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3218707; hg19: chr11-108114727;