11-108247071-C-T

Position:

chr11-108247071-C-T

Variant summary

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

The NM_000051.4(ATM):c.1009C>T(p.Arg337Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000892 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19B:2

Conservation

PhyloP100: 4.25

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	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.1009C>T	p.Arg337Cys	missense_variant	8/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.1009C>T	p.Arg337Cys	missense_variant	8/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251170

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461586

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000872

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000171

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000104

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:19Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2021	In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 17393301 (2008), 28569218 (2017), 28779002 (2017), 30537493 (2018), 30303537 (2019)), prostate cancer (PMID: 29368341 (2018)), and chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as unaffected controls (PMIDs: 28779002 (2017), 30303537 (2019)). It has also been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.0002 (7/35394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, prostate, pancreatic, and other cancers (Broeks et al., 2008, Decker et al., 2017, Tiao et al., 2017, Isaacsson Velho et al., 2018, Walsh et al., 2018, Elbracht et al., 2021; Yu et al., 2022); This variant is associated with the following publications: (PMID: 27896999, 28569218, 28870692, 22529920, 17393301, 19781682, 22420423, 27720647, 24463458, 28500398, 27844328, 28779002, 29368341, 29449433, 23778141, 29872864, 28652578, 29106415, 29316426, 30197789, 30662270, 30814645, 31843900, 30537493, 33280026, 30311369, 32183301, 30303537, 34477817, 35047863) -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2023	This missense variant replaces arginine with cysteine at codon 337 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 and prostate cancer (PMID: 17393301, 19781682, 20305132, 23555315, 28779002, 29368341, 34477817), chronic lymphocytic leukemia (PMID: 28652578) and in unaffected controls (PMID: 28652578, 28779002). In addition, a large international case-control study reported this variant in 4/60462 breast cancer cases and 10/53451 controls (OR=0.354, 95%, CI 0.111 to 1.128, p-value=0.105; PMID: 33471991). This variant has been identified in 26/282550 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	May 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2023	The p.R337C variant (also known as c.1009C>T), located in coding exon 7 of the ATM gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. Using multiple in silico tools, this alteration was predicted to have some potential for functional significance (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). This alteration has been reported in an individual with unilateral breast cancer diagnosed before 50 years of age and an individual with prostate cancer (Broeks A et al. Breast Cancer Res. Treat. 2008 Jan;107:243-8; Velho P et al. Prostate 2018 04;78(5):401-407). This alteration has also been reported both in affected cancer individuals and in unaffected controls across several studies (Decker B et al. J Med Genet, 2017 11;54:732-741; Tiao G et al. Leukemia, 2017 10;31:2244-2247; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 27, 2024	- -

Ataxia-telangiectasia syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 16, 2023	The ATM c.1009C>T (p.Arg337Cys) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 19781682, 30303537). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2023	Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.000092 (i.e. 26 heterozygotes) in 282550 control chromosomes gnomAD. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in numerous individuals affected with Breast Cancer and other tumor phenotypes that belong to the HBOC cancer spectrum (e.g. Broeks_2008, Tavtigian_2009, Bernstein_2010, Karlsson_2021, Elbracht_2021), however, it was also reported in controls (Karlsson_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 4/60466 cases, but was also found in 10/53461 controls (Dorling_2021 through LOVD). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH2 c.2021G>A, p.Gly674Asp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function and no occurrence of the variant in individuals affected with Ataxia-Telangiectasia has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 17393301, 33471991, 34477817, 33280026, 26085511, 33436325, 36315919, 27322425, 19781682, 28652578). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant with a predominant consensus as VUS (n=13); two submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Arg337Cys variant was identified in 1 of 874 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Broeks 2008). The variant was also identified in dbSNP (ID: rs138398778) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics), Clinvitae, Cosmic, and MutDB databases. The variant was not identified in the COGR or LOVD 3.0 databases. The variant was identified in control databases in 23 of 276952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 6 of 34376 chromosomes (freq: 0.0002), European in 13 of 126526 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg337 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;.

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-1.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.94, 0.97

MVP

0.95

MPC

0.68

ClinPred

0.57

GERP RS

5.7

Varity_R

0.49

gMVP

0.57

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