11-108345882-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000051.4(ATM):c.8558C>T(p.Thr2853Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T2853R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:1O:1

Conservation

PhyloP100: 7.89

Publications

28 publications found

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:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 49 uncertain in NM_000051.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8558C>T	p.Thr2853Met	missense_variant	Exon 58 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8558C>T	p.Thr2853Met	missense_variant	Exon 58 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

251092

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461456

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33456

American (AMR)

AF:

0.0000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39632

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111748

Other (OTH)

AF:

0.0000497

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41428

American (AMR)

AF:

0.000131

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.633

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000378

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jun 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26837699, 25503501, 26689913, 28779002, 28188106, 27304073, 25042771, 28652578, 30613976, 33436325, 34371384, 35039564, 32522261, 35365198, 30253992, 23532176, 36568162, 33471991, 36446039, 35171259, 37262986) -

Hereditary cancer-predisposing syndrome

Uncertain:3

Oct 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T2853M variant (also known as c.8558C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8558. The threonine at codon 2853 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 13087 breast cancer cases from the UK (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). This variant was also identified in 1 of 1009 Chinese patients with a personal history of pancreatic ductal adenocarcinoma (Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces threonine with methionine at codon 2853 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 33471991, 35039564), pancreatic cancer (PMID: 34371384), or chronic lymphocytic leukemia (PMID: 26837699), as well as in unaffected controls (PMID: 33471991, 35365198). This variant has been identified in 15/282472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 18, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Uncertain:2

Nov 14, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATM c.8558C>T (p.Thr2853Met) results in a non-conservative amino acid change located in the phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251092 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.2e-05 vs 0.001), allowing no conclusion about variant significance. c.8558C>T has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast cancer (e.g. Rizzolo_2019, Dorling_2021, Eygelaar_2022, van der Merwe_2022), early-onset prostate cancer (Trendowski_2022), and other types of cancer (e.g. Nadeu_2016, Yin_2022). However, it has also been reported in unaffected control individuals (e.g. Dorling_2021, Renault_2022). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 35039564, 25042771, 26837699, 35365198, 30613976, 35171259, 36568162, 36446039, 37262986). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome

Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2853 of the ATM protein (p.Thr2853Met). This variant is present in population databases (rs141534716, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, gastric cancer, pancreatic cancer, and/or prostate cancer (PMID: 26689913, 26837699, 30613976, 33436325, 34371384, 35171259). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in ATM in an individual who was not affected with recessive ATM-related conditions (internal data). This suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 142249). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial cancer of breast

Uncertain:1Benign:1

Mar 07, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 20, 2024

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely 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]. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATM-related disorder

Uncertain:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM c.8558C>T variant is predicted to result in the amino acid substitution p.Thr2853Met. This variant has been reported in individuals with a history of breast cancer (Table S5, Decker et al. 2017. PubMed ID: 28779002; Dorling et al. 2021. PubMed ID: 33471991; Table 2, Eygelaar et al. 2022. PubMed ID: 35039564), pancreatic cancer (Bono et al. 2021. PubMed ID: 34371384), or chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699); but has also been reported in control individuals (Dorling et al. 2021. PubMed ID: 33471991). Of note, a different missense variant at this same position (p.Thr2853Arg) has been reported in a patient with breast cancer (Supplementary Table 1, Maxwell et al. 2015. PubMed ID: 25503501). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is listed in ClinVar by multiple laboratories as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142249/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM p.Thr2853Met variant was identified in 1 of 796 proband chromosomes (frequency: 0.001) from individuals or families with chronic lymphocytic leukemia (Nadeu 2015). The variant was also identified in dbSNP (ID: rs141534716) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and two other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 17 of 276798 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001), Latino in 1 of 34376 chromosomes (freq: 0.00003), European in 9 of 126386 chromosomes (freq: 0.00007), East Asian in 2 of 18860 chromosomes (freq: 0.0001), Finnish in 1 of 25776 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the Other or Ashkenazi Jewish populations. The p.Thr2853 residue is conserved across mammals and other organisms and 5 of 5 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 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, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

7.9

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.1

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.93

MVP

0.97

MPC

0.59

ClinPred

0.86

GERP RS

5.5

Varity_R

0.86

gMVP

0.86

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over