11-108256239-C-T

Position:

chr11-108256239-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000051.4(ATM):c.2149C>T(p.Arg717Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,606,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:1

Conservation

PhyloP100: 3.35

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:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.2149C>T	p.Arg717Trp	missense_variant	14/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2149C>T	p.Arg717Trp	missense_variant	14/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

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

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250562

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1454610

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

723664

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000235

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000390

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2024	Observed in individuals with breast cancer, ovarian cancer, or leukemia and also in unaffected controls (PMID: 26689913, 25186627, 28652578, 30303537, 37013556, 32885271, 36200007); 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; This variant is associated with the following publications: (PMID: 30303537, 24416720, 26689913, 27994516, 12697903, 30287823, 28652578, 25186627, 31159747, 32566746, 31942411, 32980694, 36200007, 33471991, 36243179, 32885271, 31214711, 37013556, 36029002, 35451682) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 05, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Arg717Trp variant was identified in 2 of 644 proband chromosomes (frequency: 0.003) from individuals or families with lymphoma and ataxia telangiectasia (Fang 2003, Petereit 2013). The variant was also identified in dbSNP (ID:rs147515380) as with uncertain significance allele, in the ClinVar and Clinvitae databases with uncertain significance by Ambry Genetics, GeneDx, Color Genomics, Invitae, and Integrated Genetics Laboratory. The variant was further identified in the Cosmic database 2X as pathogenic in tissues derived from a Lymphoid neoplasm and a carcinoid-endocrine tumor. The variant was not identified in the 1000 Genomes Project nor was it identified in the dbSNP, COGR, MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8596 European American and 1 of 4402 African American alleles. In addition, the variant was identified in control databases in 12 of 276362 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 24012 chromosomes (freq: 0.0001), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 1 of 6432 chromosomes (freq: 0.0002), Latino in 2 of 34310 chromosomes (freq: 0.00006), European Non-Finnish in 4 of 126346 chromosomes (freq: 0.00003), East Asian in 1 of 18702 chromosomes (freq: 0.00005), and South Asian in 1 of 30692 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, European Finnish, populations. Although the p.Arg717 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg717Trp variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 27, 2022	The p.R717W variant (also known as c.2149C>T), located in coding exon 13 of the ATM gene, results from a C to T substitution at nucleotide position 2149. The arginine at codon 717 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in a Caucasian cancer patient undergoing radiation therapy, 1/1197 individuals from Greece, Romania and Turkey undergoing evaluation for inherited cancer predisposition, in a colorectal cancer cohort from Macedonia, and in multiple breast cancer cohorts (Petereit DG et al. Front Oncol. 2013 Dec;3:318; Tung N et al. Cancer 2015 Jan;121(1):25-33; Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535; Staninova-Stojovska M et al. Balkan J. Med. Genet. 2019 Dec;22(2):5-16; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). In one study, this variant was reported in 3/60,466 breast cancer cases and in 6/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In studies of Japanese breast, prostate and pancreatic cancer cohorts, this alteration was not observed in patients affected with cancer but seen in multiple unaffected controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Oct 17, 2023	This missense variant replaces arginine with tryptophan at codon 717 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer and control individuals (PMID: 25186627, 30287823, 30303537, 31159747, 32980694, 32885271, 33471991, 36200007), and pancreatic cancer (PMID: 27994516). In a case-control study conducted in Japan, this variant was reported in 3/11241 female and 1/12490 male controls, and absent in 7051 female and 53 male breast cancer cases (PMID: 30287823). In a large international case-control study, this variant was reported in 3/60463 breast cancer cases and 6/53455 controls (OR=0.442, 95%CI 0.111 to 1.768, p-value=0.321; PMID: 33471991). This variant has been identified in 11/281892 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2021	- -

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 717 of the ATM protein (p.Arg717Trp). This variant is present in population databases (rs147515380, gnomAD 0.01%). This missense change has been observed in individual(s) with chronic lymphocytic leukemia and biliary tract cancer and/or personal or family history of breast and/or ovarian cancer (PMID: 30303537, 31159747, 35451682, 36029002, 36243179). ClinVar contains an entry for this variant (Variation ID: 140879). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 36029002). 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. -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 07, 2024	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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	A variant of uncertain significance was detected in the ATM gene (c.2149C>T). This missense variant replaces arginine with tryptophan at codon 717 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function and they show pathogenic computational verdict based on 9 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster and SIFT vs 3 benign predictions from BayesDel_addAF, DEOGEN2 and PrimateAI. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with pancreatic cancer (PMID: 27994516), lymphoma (PMID: 12697903), unspecified cancer (PMID: 24416720) or polyposis (PMID: 31942411). This variant has been identified in 11/281892 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. Heterozygous pathogenic/likely pathogenic mutations in the ATM gene cause breast cancer susceptibility (OMIM 114480). -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Cancer Genomics Group, Japanese Foundation For Cancer Research	May 01, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 09, 2024	According to the ACMG standard criteria we chose this criterion: PM2 (supporting pathogenic): PM2 als dummy -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 11, 2022

Variant summary: ATM c.2149C>T (p.Arg717Trp) 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 4e-05 in 250562 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.2149C>T has been reported in the literature in individuals affected with personal and/or family history of breast and/or ovarian cancer, and other tumor phenotypes (e.g. Fang_2013, Petereit_2013, Girard_2019, Tsaousis_2019, Dorling_2021,), however it was also reported in several healthy controls (e.g. Momozawa_2018, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

.;T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D;.

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.45

T;T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.99

.;D;D

Vest4

0.68, 0.66

MVP

0.93

MPC

0.57

ClinPred

0.39

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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