11-108330281-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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:14

Conservation

PhyloP100: 1.33

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 made for transcript

Verdict is Uncertain_significance. Variant got 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, 15 uncertain in NM_000051.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7375C>G	p.Arg2459Gly	missense_variant	50/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.7375C>G	p.Arg2459Gly	missense_variant	50/63		NM_000051.4	P1

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251258

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135788

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000956

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2021	The frequency of this variant in the general population, 0.000087 (3/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast (PMIDs: 33128190 (2021) and 35264596 (2022)), ovarian (PMIDs: 24448499 (2014) and 26689913 (2015)), colorectal (PMID: 28135145 (2017)), prostate (PMID: 33436325 (2021)), and lung cancers (PMID: 28843361 (2017)), as well as in an individual who met clinical criteria for neurofibromatosis type 1 (NF1) (PMID: 28051113 (2017)). In a large scale breast cancer association study, the variant was observed in control individuals and breast cancer cases (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). In addition, this variant was observed with 2 other pathogenic ATM variants in an individual affected with ataxia-telangiectasia (AT) (PMID: 21665257 (2011)), which suggests this variant may not be the primary cause of disease. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Franklin by Genoox	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	ATM: PM1, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	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) -

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2023	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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2022	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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, 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; Color Health internal data), ovarian cancer (PMID: 24448499, 26689913, 33280026), lung cancer (PMID: 28843361), and colorectal cancer (PMID: 28135145; Color Health internal data). 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. -

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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). ClinVar contains an entry for this variant (Variation ID: 181982). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 13, 2021

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 27, 2023

- -

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

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

MutationTaster

Benign

1.0

D;D;D

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

Polyphen

1.0

D;D

Vest4

0.75

MutPred

0.66

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);

MVP

0.96

MPC

0.64

ClinPred

0.95

GERP RS

4.7

Varity_R

0.81

gMVP

0.69

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over