chr11-108289015-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_000051.4(ATM):c.4148C>T(p.Ser1383Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,348 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). Synonymous variant affecting the same amino acid position (i.e. S1383S) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21B:3

Conservation

PhyloP100: 7.36

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

BP6

Variant 11-108289015-C-T is Benign according to our data. Variant chr11-108289015-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127382.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=13}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.4148C>T	p.Ser1383Leu	missense_variant	Exon 28 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.4148C>T	p.Ser1383Leu	missense_variant	Exon 28 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000358

AC:

AN:

251290

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461222

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33460

American (AMR)

AF:

0.0000895

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1111622

Other (OTH)

AF:

0.0000331

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41436

American (AMR)

AF:

0.000262

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000818

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:21Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:8

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.4148C>T (p.Ser1383Leu) variant has been reported in the published literature in individuals/families affected with breast cancer (PMIDs: 38874686 (2024), 35264596 (2022), 32885271 (2021), 31206626 (2019), 30306255 (2018), 28503720 (2017), 26976419 (2016), 19781682 (2009), 14695186 (2003), 11505391 (2001)), ovarian cancer (PMID: 30441849 (2018)), and various other cancers (PMIDs: 26689913 (2015), 26837699 (2016), 33436325 (2021), 35467778 (2022), 37536918 (2023)). In a large breast cancer association study, the variant was identified in individuals with breast cancer and in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/)). One functional study suggested this variant possibly increased the chromosomal radiosensitivity of a breast cancer cell line (PMID: 15101044 (2004)). The frequency of this variant in the general population, 0.000047 (6/129022 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 24, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 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; Observed in individuals with breast or prostate cancer, but also in unaffected controls (PMID: 11505391, 14695186, 15101044, 19781682, 26976419, 28503720, 30306255, 31206626, 33436325, 33471991, 35467778, 35264596, 35534704, 35957908); This variant is associated with the following publications: (PMID: 26689913, 26976419, 17333338, 14695186, 11505391, 21787400, 15101044, 20346647, 19683821, 26837699, 28503720, 28779002, 30306255, 29641532, 29483558, 19781682, 34426522, 33436325, 30441849, 33471991, 35264596, 30197789, 31206626, 34262154, 35467778, 37529773, 38874686, 35534704, 35957908, 37536918) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome

Uncertain:3Benign:2

Apr 28, 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. -

Dec 22, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:3

Nov 12, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4148C>T, in exon 28 that results in an amino acid change, p.Ser1383Leu. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP rs141087784). The p.Ser1383Leu change has been reported in individuals with chronic lymphocytic leukemia, lung cancer, and breast cancer (PMIDs: 11505391, 19781682, 26976419, 14695186, 26837699, 26689913, 15101044). One of the reported breast cancer cases was also identified to have another sequence change in ATM, p.Asp1853Val (PMID: 19781682). The p.Ser1383Leu change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Ser1383Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1383Leu change remains unknown at this time. -

Feb 27, 2025

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.4148C>T (p.Ser1383Leu) results in a non-conservative amino acid change in 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 3.6e-05 in 251290 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4148C>T has been reported in the literature in individuals affected with breast cancer (Teraoka_2001, Angele_2003, Guttierez-Enriquez_2004, Tavtigian_2009, Tung_2015, Rummel_2017, Weitzel_2019), ovarian cancer (Koczkowska_2018), HBOC families testing negative for BRCA1/2 (Bonache_2018), prostate cancer (Brady_2022), lung adenocarcinoma in the TGCA cohort (Lu_2015), and CLL (Nadeu_2016), but it was also found in controls (e.g. Dalmasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, and was found in 6/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another (likely) pathogenic variant in an individual undergoing testing due to a personal and family history of breast cancer has been reported at our laboratory (BRCA2 c.9256_9256+1delinsTA), providing supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Gutierrez-Enriquez_2004). The following publications have been ascertained in the context of this evaluation (PMID: 14695186, 30197789, 30306255, 35467778, 34262154, 33471991, 15101044, 20346647, 34426522, 30441849, 26689913, 26837699, 28503720, 19781682, 11505391, 26976419, 31206626, 38697030). ClinVar contains an entry for this variant (Variation ID: 127382). 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

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Feb 10, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1383L variant (also known as c.4148C>T), located in coding exon 27 of the ATM gene, results from a C to T substitution at nucleotide position 4148. The serine at codon 1383 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in individuals diagnosed with breast, ovarian and prostate cancer (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Rummel SK et al. Breast Cancer Res Treat, 2017 Aug;164:593-601; Koczkowska M et al. Cancers (Basel), 2018 Nov;10:; Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Apr 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with leucine at codon 1383 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: 11505391, 14695186, 15101044, 19781682, 20346647, 21787400, 26976419, 28503720, 35264596), prostate cancer (PMID: 35467778) lung adenocarcinoma (PMID: 26689913), or chronic lymphocytic leukemia (PMID: 26837699). In a large breast cancer case-control meta-analysis, this variant was reported in 5/60466 cases and 6/53455 controls (OR=0.737, 95%CI 0.225 to 2.414, p-value=0.765; PMID: 33471991). This variant has also been identified in 11/282674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on protein function that has been observed in affected individuals as well as in the general population. 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. -

Familial cancer of breast

Uncertain:1Benign:1

Apr 17, 2025

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]. -

Feb 25, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Mar 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Uncertain:1

Jan 20, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM2, PP3 -

ATM-related disorder

Uncertain:1

Jul 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM c.4148C>T variant is predicted to result in the amino acid substitution p.Ser1383Leu. This variant has been reported in individuals with a history of breast cancer (Table 1, Teraoka et al. 2001. PubMed ID: 11505391; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A2, Tung et al. 2016. PubMed ID: 26976419; Table 1, Angèle et al. 2003. PubMed ID: 14695186), prostate cancer (reported as uncertain in Table S4, Karlsson et al. 2021. PubMed ID: 33436325), ovarian cancer (Koczkowska M et al. 2018. PubMed ID: 30441849), and chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699), but without data regarding segregation of the variant in affected individuals. Furthermore, in at least one individual, an additional variant was identified in ATM (p.Asp1853Val) (Table A2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127382/). 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.Ser1383Leu variant was identified in 7 of 7698 proband chromosomes (frequency: 0.0009) from individuals or families with breast cancer or chronic lymphocytic leukemia and was not identified in 5276 control chromosomes from healthy individuals (Angele 2003, Gutierrez Enriquez 2004, Nadeu 2015, Tavtigian-2009, Teraoka 2001, Tung 2016). The variant was also identified in dbSNP (ID: rs141087784) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and LOVD 3.0 database (1x). The variant was identified in control databases in 11 of 277016 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004), Other in 2 of 6462 chromosomes (freq: 0.0003), Latino in 1 of 34406 chromosomes (freq: 0.00003), and European in 7 of 126544 chromosomes (freq: 0.00006); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. A study using cell lines from breast cancer cases carrying the variant showed no difference in the constitutive ATM protein level after exposure to ionizing radiation (Angele 2003). The p.Ser1383 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.9

M;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.8

D;D;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.90

MVP

0.94

MPC

0.14

ClinPred

0.83

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.60

Mutation Taster

=5/95

disease causing

(source)

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr11-108289015-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over