chr11-108247060-C-T

Variant names:

• chr11-108247060-C-T
• rs28904919
• NM_000051.4:c.998C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000051.4(ATM):​c.998C>T​(p.Ser333Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,876 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S333C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:28 O:1
• Conservation: PhyloP100: 3.49
• Publications: 42 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0085556805).
• BP6: Variant 11-108247060-C-T is Benign according to our data. Variant chr11-108247060-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127471.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00135 (206/152300) while in subpopulation AMR AF = 0.00405 (62/15300). AF 95% confidence interval is 0.00324. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.998C>T	p.Ser333Phe	missense_variant	Exon 8 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.998C>T	p.Ser333Phe	missense_variant	Exon 8 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 251168 AF XY: 0.00141

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00144 AC: 2099 AN: 1461576 Hom.: 4 Cov.: 31 AF XY: 0.00138 AC XY: 1007 AN XY: 727076

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.00374 AC: 167 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00403 AC: 215 AN: 53408

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00147 AC: 1630 AN: 1111872

Other (OTH) AF: 0.00134 AC: 81 AN: 60376

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74470

African (AFR) AF: 0.000313 AC: 13 AN: 41546

American (AMR) AF: 0.00405 AC: 62 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00133 Hom.: 1

Bravo AF: 0.00137

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00136

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:28 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:10

Mar 17, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PS3:Supporting, BP1, BS2 -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.998C>T affects a conserved nucleotide, resulting in an amino acid change from Ser to Phe. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO and MutationTaster not captured due to low reliability index).This variant was found in patients with MCL, idiopathic juxtafoveolar retinal telangiectasia, breast cancer, CLL, and CRC in germline and in tumor samples. However, co-segregation data were not available in these studies to establish causality of this variant in many studies. In one breast cancer family published in the literature, only the index patient had the variant while 3 affected sisters did not (Tommiska_2006), suggesting that this variant was not causative. The variant of interest was also found in 165/125148 control chromosomes at a frequency of 0.0013184. Specifically, in Finnish control population, MAF of this variant is 0.004548, which is greater than the estimated maximal expected frequency of a pathogenic ATM allele for AT (0.003953) or breast cancer (0.0005001), suggesting this variant is benign. In addition, multiple clinical laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant was classified as Likely Benign until additional information is available. -

not specified Benign:6 Other:1

Dec 17, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Ser333Phe variant was identified in 9 (1 homozygous) of 2296 proband chromosomes (frequency: 0.004) from Finnish and American individuals or families with non-BRCA1/2 breast cancer, breast cancer, early onset and familial CRC, and individuals undergoing radiation therapy, and was identified in 37 of8118 chromosomes from healthy (race matched controls) (Petereit 2013, Tommiska 2006, Teraoka 2001, Tanskanen 2015). Segregation studies in 1 family were negative, as the proband’s 3 affected sisters were non-carriers (Tommiska 2006). The variant was also identified in dbSNP (ID: rs28904919) “With Likely benign allele”, ClinVar (classified benign by Invitae, likely benign by GeneDx, Ambry Genetics and ARUP, and classification not provided by ITMI), Clinvitae (3x), Cosmic (2x in a hemangioblastoma and adnexal tumour) and not in MutDB and LOVD 3.0. The variant was identified in control databases in 439 of 276964 chromosomes (1 homozygous) 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 8 of 24024 chromosomes (freq: 0.0003), Other in 9 of 6462 chromosomes (freq: 0.001), Latino in 125 (1 homozygous) of 34380 chromosomes (freq: 0.004), European Non-Finnish in 209 of 126534 chromosomes (freq: 0.002), European Finnish in 88 of 25784 chromosomes (freq: 0.003), while not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ser333 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume 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. -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 20, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2017

GeneDx

Significance: Likely 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. -

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.998C>T (p.Ser333Phe) missense variant has an allele frequency of 0.16%, (421/268,078 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.35%, (123/35,062 alleles) in the Latino / Admixed American subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 1 individual of the gnomAD v2.1.1 non-neuro dataset and in 1 individual older than 75 year, not affected from ataxia telangiectasia, from the Spanish ATM working group cancer cohort (BS2_Supporting, PMID: 33280026). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. However, the in silico protein effect prediction for this missense variant is inconclusive (no predictive criterion met). Therefore, the variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting (PMID: 33280026). -

Nov 04, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP2_Strong, BP4 c.998C>T, located in exon 8 of the ATM gene, is predicted to result in the substitution of serine by phenylalanine at codon 333, p.(Ser333Phe). The variant allele was found in 123/35062 alleles, with a filter allele frequency of 0.30% at 99% confidence, within the Latino population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.073) suggests that it does not affect the protein function (BP4). To our knowledge, no well-established functional studies have been reported for this variant. It has been reported in homozygous state in at least 3 ataxia-telangiectasia unaffected individuals (PMID: 33280026, 25749350 and gnomAD non-neuro dataset) (BP2_Strong). This variant has been reported in the ClinVar database (1x uncertain significance, 22x likely benign, 5x benign) and in LOVD (8x likely benign, 1x benign), Based on currently available information, the variant c.998C>T should be considered a benign variant, according to ACMG Classification Rules Specified for ATM by ClinGen, v1.1. -

Nov 18, 2021

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. -

Feb 18, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:3

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2020

Natera, Inc.

Significance: Likely 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

- -

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial cancer of breast Benign:2

Jan 10, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breast and/or ovarian cancer Benign:1

Jun 22, 2023

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;T
Eigen	Benign	0.058
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;.
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;M;M
PhyloP100		3.5
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;N;N
REVEL	Benign	0.073
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.61	.;P;P
Vest4		0.48, 0.54
MVP		0.86
MPC		0.38
ClinPred		0.033	T
GERP RS		3.9
Varity_R		0.082
gMVP		0.44
Mutation Taster		=96/4	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: rs28904919; hg19: chr11-108117787; COSMIC: COSV53740555; COSMIC: COSV53740555;