11-108331498-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.7570G>C(p.Ala2524Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,158 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2524S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.69

Publications

17 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: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 48 uncertain in NM_000051.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 11-108331498-G-C is Pathogenic according to our data. Variant chr11-108331498-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 187613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATM	NM_000051.4	MANE Select	c.7570G>C	p.Ala2524Pro	missense	Exon 51 of 63	NP_000042.3
ATM	NM_001351834.2		c.7570G>C	p.Ala2524Pro	missense	Exon 52 of 64	NP_001338763.1
C11orf65	NR_147053.3		n.2442C>G		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATM	ENST00000675843.1	MANE Select	c.7570G>C	p.Ala2524Pro	missense	Exon 51 of 63	ENSP00000501606.1
ATM	ENST00000452508.7	TSL:1	c.7570G>C	p.Ala2524Pro	missense	Exon 52 of 64	ENSP00000388058.2
ATM	ENST00000527805.6	TSL:1	n.*2634G>C		non_coding_transcript_exon	Exon 49 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000952

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251298

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.000244

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111764

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151792

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41316

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.0000952

AC:

AN:

10500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:1

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2524 of the ATM protein (p.Ala2524Pro). This variant is present in population databases (rs769142993, gnomAD 0.03%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or ATM-related cancers (PMID: 10980530, 11897822, 16622469). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 187613). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 17166884, 22071889). For these reasons, this variant has been classified as Pathogenic.

not provided

Pathogenic:1

Feb 20, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the compound heterozygous or homozygous state in multiple unrelated patients with ataxia-telangiectasia, and confirmed to be on the opposite allele (in trans) with a pathogenic variant in at least one individual (PMID: 10980530, 11897822, 22071889); Published functional studies suggest a damaging effect: defective kinase activity (PMID: 17166884, 22071889); 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: 16622469, 16914028, 30927251, 32853339, 35095854, 33436325, 32183364, 29922827, 36467798, 20346647, 11897822, 10980530, 19224889, 22071889, 17166884, 23532176, 36551643, 36161273, 37578974)

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 21, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A2524P variant (also known as c.7570G>C), located in coding exon 50 of the ATM gene, results from a G to C substitution at nucleotide position 7570. The alanine at codon 2524 is replaced by proline, an amino acid with highly similar properties. This variant has been identified in the homozygous state and/or in conjunction with other ATM variant(s) in individual(s) with features consistent with ataxia telangiectasia (AT) (Allinen M et al. J Med Genet. 2002 Mar;39(3):192-6). This alteration has also been observed as heterozygous in multiple individuals diagnosed with breast or prostate cancer (Allinen M et al. J Med Genet. 2002 Mar;39(3):192-6; Bubien V et al. Genes Chromosomes Cancer. 2017 Nov;56(11):788-799; Nurmi A et al. Int. J. Cancer, 2019 11;145:2692-2700; Rantapero T et al. Genes (Basel), 2020 03;11:; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). One functional study demonstrated that this alteration leads to a stable protein that is defective in kinase activity (Pylkas K et al. Carcinogenesis. 2007 May;28(5):1040-5). A second functional study demonstrated that this alteration leads to a significantly decreased response to ionizing radiation that is similar to that of a control AT cell line (Jacquemin V et al. Eur J Hum Genet. 2012 Mar;20(3):305-12). 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 majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.6

PhyloP100

9.7

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.97

MutPred

0.90

Loss of MoRF binding (P = 0.0532)

MVP

0.99

MPC

0.65

ClinPred

0.96

GERP RS

5.4

Varity_R

0.83

gMVP

0.85

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over