11-108247071-C-T

Variant names:

• chr11-108247071-C-T
• rs138398778
• NM_000051.4:c.1009C>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).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20 B:2
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.1009C>T	p.Arg337Cys	missense_variant	Exon 8 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.1009C>T	p.Arg337Cys	missense_variant	Exon 8 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152102 Hom.: 0 Cov.: 32

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: 22 AN: 251170 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135772

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.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56 AN XY: 727088

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: 26 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74306

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.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Oct 16, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

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; Observed in individuals with breast, prostate, pancreatic, and other cancers, but also in unaffected controls (PMID: 17393301, 28779002, 28652578, 29368341, 30311369, 34477817, 35047863, 36315919, 34262154, 34326862, 33471991, 33436325); 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, 36315919, 34262154, 34326862, 38451242, 33471991, 33436325, 37626821) -

May 30, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 uninformative in assessment of its pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Computational tools predict that this variant is damaging. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Uncertain:4

Feb 27, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2024

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 cysteine at codon 337 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. 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. -

Apr 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 05, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Ataxia-telangiectasia syndrome Uncertain:3 Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

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

- -

Familial cancer of breast Uncertain:3

Oct 16, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 27, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2021

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2023

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.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. -

Sep 01, 2019

King Laboratory, University of Washington

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Uncertain significance allele”, 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	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	.;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;.
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Uncertain	0.60	T
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	D
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

Other links and lift over

dbSNP: rs138398778; hg19: chr11-108117798; COSMIC: COSV53723836; COSMIC: COSV53723836;