11-108227865-T-C

Variant names:

• chr11-108227865-T-C
• rs3218690
• NM_000051.4:c.162T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000051.4(ATM):​c.162T>C​(p.Tyr54Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,613,016 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:31
• Conservation: PhyloP100: -1.85
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-108227865-T-C is Benign according to our data. Variant chr11-108227865-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132757.
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (299/152336) while in subpopulation NFE AF = 0.00348 (237/68020). AF 95% confidence interval is 0.00312. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.162T>C	p.Tyr54Tyr	synonymous	Exon 3 of 63	NP_000042.3
	ATM	NM_001351834.2		c.162T>C	p.Tyr54Tyr	synonymous	Exon 4 of 64	NP_001338763.1
	ATM	NM_001351835.2		c.162T>C	p.Tyr54Tyr	synonymous	Exon 3 of 4	NP_001338764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.162T>C	p.Tyr54Tyr	synonymous	Exon 3 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.162T>C	p.Tyr54Tyr	synonymous	Exon 4 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.162T>C	p.Tyr54Tyr	synonymous	Exon 3 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00173 AC: 433 AN: 250966 AF XY: 0.00189

Gnomad AFR exome AF: 0.000742

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00267 AC: 3903 AN: 1460680 Hom.: 6 Cov.: 31 AF XY: 0.00260 AC XY: 1887 AN XY: 726590

African (AFR) AF: 0.000449 AC: 15 AN: 33444

American (AMR) AF: 0.000537 AC: 24 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 67 AN: 26120

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

South Asian (SAS) AF: 0.000686 AC: 59 AN: 85986

European-Finnish (FIN) AF: 0.00206 AC: 110 AN: 53396

Middle Eastern (MID) AF: 0.00144 AC: 8 AN: 5540

European-Non Finnish (NFE) AF: 0.00315 AC: 3506 AN: 1111576

Other (OTH) AF: 0.00189 AC: 114 AN: 60312

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74504

African (AFR) AF: 0.000505 AC: 21 AN: 41584

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00348 AC: 237 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00249 Hom.: 1

Bravo AF: 0.00172

Asia WGS AF: 0.000867 AC: 3 AN: 3474

EpiCase AF: 0.00338

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:31

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:9

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Tyr54= variant was identified in 8 of 1966 proband chromosomes (frequency: 0.004) from Finnish, Dutch and Austrian individuals or families with (BRCA1/2 negative) breast cancer or HBOC, American/non America Indian individuals undergoing radiation therapy, and Jewish children with Hodgkin’s disease (Tommiska_2006_16914028, Thorstenson_2003_12810666, Petereit_2013_24416720, Liberzon_2004_14735203, Broeks_2008_17393301). The variant was identified in dbSNP (ID: rs3218690) “With other allele”, ClinVar (conflicting interpretations of pathogenicity; submitters: benign by Invitae and GeneDx, likely benign by Ambry Genetics and Genetic Services Laboratory (University of Chicago), and uncertain significance by Praxis fur Humangenetik Tuebingen), Clinvitae (4x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0. The variant was also identified in control databases in 486 (1 homozygous) of 276848 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 14 of 24010 chromosomes (freq: 0.0006), Other in 13 of 6460 chromosomes (freq: 0.002), Latino in 12 of 34408 chromosomes (freq: 0.0003), European Non-Finnish in 359 (1 homozygous) of 126590 chromosomes (freq: 0.003), Ashkenazi Jewish in 24 of 10142 chromosomes (freq: 0.002), European Finnish in 43 of 25762 chromosomes (freq: 0.002), and South Asian in 21 of 30610 chromosomes (freq: 0.0007) while not observed in the East Asian population. The p.Tyr54= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Jan 11, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This c.162T>C variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 208/121226 control chromosomes (including the large and broad populations of ExAC) at a frequency of 0.0017158, which does not exceed the maximal expected frequency of a pathogenic allele (0.0039528) in this gene. However, the possibility that this variant can still represents as a rare polymorphism cannot be ruled out from the comparison. The variant is more common in European (Non-Finnish) population where its allele frequency is 0.25% (167/66625 chromosomes) including one homozygous occurrence. The homozygote is suggestive of a benign outcome with respect to early onset recessive phenotype A-T. [Penetrance of variants causing A-T is not exactly known.] This variant has been found in patients with A-T, breast and/or ovarian cancer, chronic lymphocytic leukemia and Hodgkins lymphoma. The publications reporting patient occurrences report this variant as polymorphism. In one A-T patient reported, the patient also carried other two potentially pathogenic variants (Buzin_2003), suggesting a benign outcome for this variant. In addition, this variant was found at similar frequencies in a small case-control study (Liberzon_2004), further supporting a benign outcome. Multiple clinical labs have classified this variant as benign/likely benign. Taken together, this variant has been classified as Benign.

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4, BP7

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 21, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 07, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ataxia-telangiectasia syndrome Uncertain:1 Benign:6

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 14, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 11, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not specified Benign:7

Aug 25, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 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 15, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

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

Dec 20, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:5

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.162T>C p.(Tyr54=) variant has an allele frequency of 0.00283 (0.23%, 334/ 118012 alleles) in the Non-Finnish European population of the gnomAD v2.1.1 non-cancer dataset (BS1; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike – MaxEntScan – NNSplice - GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). This silent variant has been identified in two ataxia telangiectasia patients, but in one case there were also detected two (likely) pathogenic variants (PMID: 12552559) and in the other one, there was also detected an homozygous truncating variant (PMID: 28898322). This, together with the high frequency of the variant in the general population suggests that c.162T>C was just a coincident polymorphism and discards the use of PM3 and PS4 criteria. Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BP4 + BP7 (PMID: 33280026).

Jun 20, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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.

Jan 03, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Apr 25, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Benign:2

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 17, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

Breast and/or ovarian cancer Benign:1

Feb 23, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.92
DANN	Benign	0.72
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3218690; hg19: chr11-108098592; COSMIC: COSV104592234;