11-108345844-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The c.8520G>C variant in ATM is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 2840 (p.Leu2840Phe). This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID:26896183, 22649200). This variant is absent from gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.464, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA348719/MONDO:0700270/020

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:10

Conservation

PhyloP100: 4.14

Publications

2 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8520G>C	p.Leu2840Phe	missense_variant	Exon 58 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8520G>C	p.Leu2840Phe	missense_variant	Exon 58 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111864

Other (OTH)

AF:

0.0000331

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000131

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jul 18, 2022

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 28, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24123366, 26896183, 22649200, 23532176, 37306523)

Oct 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.8520G>C (p.Leu2840Phe) variant has been reported in the published literature in a homozygous individual with ataxia telangiectasia who's biochemical evidence confirmed protein impairment (PMID: 22649200 (2012)). The frequency of this variant in the general population, 0.000013 (2/152098 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.

Ataxia-telangiectasia syndrome

Uncertain:2

May 28, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2840 of the ATM protein (p.Leu2840Phe). This variant is present in population databases (rs752652869, gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 22649200). ClinVar contains an entry for this variant (Variation ID: 221124). 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 not expected to disrupt ATM protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 26896183). 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.

Hereditary cancer-predisposing syndrome

Uncertain:2

Aug 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L2840F variant (also known as c.8520G>C), located in coding exon 57 of the ATM gene, results from a G to C substitution at nucleotide position 8520. The leucine at codon 2840 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in the homozygous state in an individual with a clinical diagnosis of ataxia-telangiectasia (Carney EF et al. J. Immunol., 2012 Jul;189:261-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Jan 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces leucine with phenylalanine at codon 2840 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. This variant has been reported in the homozygous state in individuals affected with ataxia-telangiectasia (PMID: 22649200, 26896183). Cells derived from these individuals have shown no detectable kinase activity. This variant has been identified in 1/246018 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.

Familial cancer of breast

Uncertain:2

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

a variant of uncertain significance in the ATM gene (p.Leu2840Phe). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2840 of the ATM protein (p.Leu2840Phe). This variant is present in population databases (rs752652869, gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 22649200). ClinVar contains an entry for this variant (Variation ID: 221124). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging";). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 22649200). 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.

Jun 06, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM-related cancer predisposition

Uncertain:1

Nov 26, 2024

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.8520G>C variant in ATM is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 2840 (p.Leu2840Phe). This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 26896183, 22649200). This variant is absent from gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.464, which is neither above nor below the thresholds predicting a damaging or benign impact on ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_Supporting)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;.

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

4.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.041

D;D

Sift4G

Benign

0.28

T;T

Vest4

0.39

ClinPred

0.85

GERP RS

3.7

Varity_R

0.18

gMVP

0.31

Mutation Taster

=37/63

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over