11-108268541-C-T

Position:

chr11-108268541-C-T

Variant summary

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

The NM_000051.4(ATM):c.2770C>T(p.Arg924Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,908 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: 0.000027 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19B:1

Conservation

PhyloP100: 1.75

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:

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.2770C>T	p.Arg924Trp	missense_variant	18/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2770C>T	p.Arg924Trp	missense_variant	18/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251442

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.000577

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:19Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	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: 28202063, 17344846, 28211887, 27978560, 28873162, 28878254, 30303537, 31432501, 33471991, 22529920, 33436325, 32658311, 31742824, 32832836, 31206626, 29522266, 23960188, 20305132, 36029002, 34284872, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2022	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2019	The ATM c.2770C>T; p.Arg924Trp variant (rs55723361) is reported in the literature in individuals affected with breast and colon cancers (Bernstein 2010, Jalkh 2017, Pearlman 2017) and diffuse large B-cell lymphoma (de Miranda 2013, Leeksma 2017), but also in control individuals (Leeksma 2017). This variant is reported in ClinVar (Variation ID: 127358), and is found in the general population with an overall allele frequency of 0.0057% (16/282842 alleles) in the Genome Aggregation Database. The arginine at codon 924 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg924Trp variant is uncertain at this time. References: Bernstein JL et al. Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. J Natl Cancer Inst. 2010 Apr 7;102(7):475-83. de Miranda NF et al. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med. 2013 Aug 26;210(9):1729-42. Jalkh N et al. Next-generation sequencing in familial breast cancer patients from Lebanon. BMC Med Genomics. 2017 Feb 15;10(1):8. Leeksma OC et al. Germline mutations predisposing to diffuse large B-cell lymphoma. Blood Cancer J. 2017 Mar 10;7(3):e541. Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017 Apr 1;3(4):464-471. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 924 of the ATM protein (p.Arg924Trp). This variant is present in population databases (rs55723361, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer, colon cancer, diffuse large B-cell lymphoma, and/or ovarian cancer (PMID: 20305132, 27978560, 28202063, 28211887, 29522266, 30303537, 31742824, 32658311). ClinVar contains an entry for this variant (Variation ID: 127358). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -

Familial cancer of breast

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 25, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 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	Jul 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 924 of the ATM protein (p.Arg924Trp). This variant is present in population databases (rs55723361, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer, colon cancer, diffuse large B-cell lymphoma, and/or ovarian cancer (PMID: 20305132, 27978560, 28202063, 28211887, 29522266, 30303537, 31742824, 32658311). ClinVar contains an entry for this variant (Variation ID: 127358). 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: 28202063, 17344846, 28211887, 27978560, 28873162, 28878254, 30303537, 31432501, 33471991, 22529920, 33436325, 32658311, 31742824, 32832836, 31206626, 29522266, 23960188, 20305132, 36029002, 34284872, 36243179). 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:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2022	The p.R924W variant (also known as c.2770C>T), located in coding exon 17 of the ATM gene, results from a C to T substitution at nucleotide position 2770. The arginine at codon 924 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in individuals diagnosed with lymphoma, breast cancer, colorectal cancer and pancreatic cancer (de Miranda NF et al. J. Exp. Med. 2013 Aug;210:1729-42; Jalkh N et al. BMC Med Genomics. 2017 Feb;10:8; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Schwartz M et al. Clin Genet, 2019 12;96:579-584; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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	curation	Sema4, Sema4	Feb 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 07, 2023	This missense variant replaces arginine with tryptophan at codon 924 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 28202063, 29522266, 30303537, 32658311, 33471991), pancreatic cancer (PMID: 31432501) and colorectal cancer (PMID: 27978560), but also in unaffected control individuals (PMID: 30303537, 31206626, 33436325, 33471991). In a large international case-control study, this variant was reported in 6/60460 breast cancer cases and 5/53456 controls (OR=1.061, 95%CI 0.324 to 3.477, p-value=1; PMID: 33471991). This variant has been identified in 16/282842 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 22, 2024

Variant summary: ATM c.2770C>T (p.Arg924Trp) 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 3e-05 in 1613908 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (3e-05 vs 0.001), allowing no conclusion about variant significance. c.2770C>T has been reported in the literature in settings of multigene panel testing of individuals affected with cancer, however without strong evidence for pathogenicity in multiple cancer types (e.g., Greenman_Nature_2007; Jalkh_BMC Med Genom_2017; Bernstein_JNCI_2010, Girard_2019, etc). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. 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: 32658311, 20305132, 22529920, 30303537, 17344846, 28202063, 33436325, 28282032, 27978560, 31432501, 31742824, 31206626, 23960188, 36243179). ClinVar contains an entry for this variant (Variation ID: 127358). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2024

The ATM c.2770C>T variant is predicted to result in the amino acid substitution p.Arg924Trp. This variant has been reported in individuals with breast cancer (Bernstein et al. 2010. PubMed ID: 20305132, Table S2; Jalkh et al. 2017. PubMed ID: 28202063, Table 2; Girard et al. 2018. PubMed ID: 30303537, Table S3), an individual with renal cancer (Greenman et al. 2007. PubMed ID: 17344846, Table S4), individuals with diffuse large B cell lymphoma (de Miranda et al. 2013. PubMed ID: 23960188, Table S3; Leeksma et al. 2017. PubMed ID: 28211887, Table 1), an individual with colorectal cancer (Pearlman et al. 2017. PubMed ID: 27978560, eTable 2), and an individual with familial pancreatic ductal adenocarcinoma (Schwartz et al. 2019. PubMed ID: 31432501, Table 1). It has also been reported in a control individual from a breast cancer cohort study (Girard et al. 2018. PubMed ID: 30303537, Table S3). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127358/). 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

0.31

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;.

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.8

.;M;M

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.78, 0.72

MVP

0.92

MPC

0.58

ClinPred

0.98

GERP RS

2.4

Varity_R

0.41

gMVP

0.62

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

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