11-108330281-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000051.4(ATM):c.7375C>G(p.Arg2459Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,040 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2459C) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:18

Conservation

PhyloP100: 1.33

Publications

20 publications found

Variant links:

COSMIC-nc: COSV99069701

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 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 36 uncertain in NM_000051.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.7375C>G	p.Arg2459Gly	missense_variant	Exon 50 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.7375C>G	p.Arg2459Gly	missense_variant	Exon 50 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000956

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251258

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1111992

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.000196

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.000956

AC:

AN:

2092

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:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Franklin by Genoox

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 16, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 30, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23585524, 24448499, 27067391, 28051113, 28843361, 26689913, 28135145, 26898890, 29752822, 33280026, 32365829, 33128190, 21665257, 33471991, 26580448, 23532176, 32986223, 33436325, 35264596)

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM: PM1, PP3

Jun 25, 2021

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ataxia-telangiectasia syndrome

Uncertain:4

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 01, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2459 of the ATM protein (p.Arg2459Gly). This variant is present in population databases (rs730881383, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian cancer, colorectal cancer, and breast cancer and ataxia telangiectasia (PMID: 21665257, 24448499, 26689913, 27067391, 28135145, 29752822, 32986223, 35534704). ClinVar contains an entry for this variant (Variation ID: 181982). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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:4

Jun 17, 2020

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7375C>G (p.Arg2459Gly) variant has an allele frequency of 0.000017 (0.002%, 4/236726 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.000088 (0.009%, 3/34256 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 (PMID: 33280026).

Feb 10, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glycine at codon 2459 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. In a large international case-control meta-analysis, this variant was reported in 12/60454 breast cancer cases and 5/53456 controls (OR=2.122, 95%CI 0.748 to 6.024, p-value=0.223; PMID: 33471991). This variant has been observed in individuals affected with breast cancer (PMID: 33128190, 33280026, 33471991, 33606809, 35264596), ovarian cancer (PMID: 24448499, 26689913, 33280026), lung cancer (PMID: 28843361), colorectal cancer (PMID: 28135145), and prostate cancer (PMID: 37436117). In addition, this variant has been observed in an individual affected with neurofibromatosis type 1, who also carried a CDKN2A whole gene deletion (PMID: 28051113). This variant has also been reported in an individual affected with ataxia-telangiectasia, although this individual was also found to have two co-occurring ATM mutations in trans (PMID: 21665257). This variant has been identified in 5/251258 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.

May 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R2459G variant (also known as c.7375C>G), located in coding exon 49 of the ATM gene, results from a C to G substitution at nucleotide position 7375. The arginine at codon 2459 is replaced by glycine, an amino acid with dissimilar properties. This variant has been detected in multiple hereditary cancer cohorts including individuals with breast and/or ovarian cancer, colorectal cancer, prostate cancer and acute lymphoblastic leukemia (Kanchi KL et al. Nat. Commun. 2014;5:3156; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Mucaki EJ et al. BMC Med Genomics, 2016 Apr;9:19; Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095; Gomes R et al. Breast Cancer Res Treat, 2021 Feb;185:851-861; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). In one study, this variant was reported in 12/60,466 breast cancer cases but also detected in 5/53,461 healthy controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been detected in a patient with ataxia telangiectasia (AT); however, this patient also carried 2 other mutations in the ATM gene, and the phase (cis or trans) of these alterations was not noted (Micol R et al. J Allergy Clin Immunol, 2011 Aug;128:382-9.e1). 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 variant remains unclear.

Jan 13, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Familial cancer of breast

Uncertain:2

Aug 05, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 27, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Apr 25, 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.7375C>G (p.Arg2459Gly) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) 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 2e-05 in 251258 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7375C>G has been observed in at least one individual affected with Breast Cancer (Bandeira_2021). This variant has also been observed in multiple studies screening for ATM variants in breast cancer, ovarian cancer, colorectal cancer, and prostate cancer without clinical data specification and genotype-phenotype correlation (Gomes_2020, Kanchi_2014, Karlsson_2021, Yurgelun_2017). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.5644C>T, p.(Arg1882*)) (Bhai_2021), providing supporting evidence for a benign role. 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: 32986223, 34326862, 33128190, 24448499, 33436325, 21665257, 28135145). ClinVar contains an entry for this variant (Variation ID: 181982). Based on the evidence outlined above, the variant was classified as uncertain significance.

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM-related disorder

Uncertain:1

Apr 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM c.7375C>G variant is predicted to result in the amino acid substitution p.Arg2459Gly. This variant has been reported in individuals with breast and/or ovarian cancer (Kanchi et al. 2014. PubMed ID: 24448499; Lu et al. 2015. PubMed ID: 26689913; Cortes-Urrea et al. 2020. PubMed ID: 32365829, Table 1; Gomes et al. 2021. PubMed ID: 33128190, Table 2; Feliubadaló et al. 2021. PubMed ID: 33280026, Table 3). It was seen in an individual who had indications of neurofibromatosis, but was predicted to have a neutral effect (Castellanos et al. 2017. PubMed ID: 28051113). It was also detected in an individual with colorectal cancer and classified as a variant of uncertain significance (Yurgelun et al. 2017. PubMed ID: 28135145, Table A4). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD, and it is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181982/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;.

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

1.3

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.75

ClinPred

0.95

GERP RS

4.7

Varity_R

0.81

gMVP

0.69

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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