NM_000051.4:c.8071C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP3

The NM_000051.4(ATM):c.8071C>T(p.Arg2691Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,613,840 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. R2691H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:14O:1

Conservation

PhyloP100: 5.74

Publications

33 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 41 uncertain in NM_000051.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8071C>T	p.Arg2691Cys	missense_variant	Exon 55 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8071C>T	p.Arg2691Cys	missense_variant	Exon 55 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000135

AC:

AN:

251216

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000428

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111780

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41532

American (AMR)

AF:

0.00105

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000292

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:5

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2691 of the ATM protein (p.Arg2691Cys). This variant is present in population databases (rs531980488, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 12935922, 15756685, 19781682, 20305132, 26689913, 29522266, 31248605, 31871109). ClinVar contains an entry for this variant (Variation ID: 133636). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. 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. -

Jun 01, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Mar 04, 2025

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 2691 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on 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 cancer (PMID: 12935922, 15756685, 19781682, 31871109, 33471991), colorectal cancer (PMID: 28135145), and thyroid cancer (PMID: 26530882). In a large international case-control meta-analysis, this variant was reported in 13/60466 breast cancer cases and 9/53461 controls (OR=1.277, 95%CI 0.546 to 2.988, p-value=0.671; PMID: 33471991). In a separate meta-analysis of breast cancer case-control studies, this variant has shown inconclusive association with disease (PMID: 19781682). This variant has also been identified in 34/251216 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. -

Aug 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R2691C variant (also known as c.8071C>T), located in coding exon 54 of the ATM gene, results from a C to T substitution at nucleotide position 8071. The arginine at codon 2691 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals diagnosed with breast cancer (Sommer SS et al. Cancer Genet Cytogenet, 2003 Sep;145:115-20; Heikkinen K et al. Int J Cancer, 2005 Aug;116:69-72; Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). It has also been reported in an individual with non-medullary thyroid cancer (Yu Y et al. Sci Rep, 2015 Nov;5:16129). This amino acid position is not well 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. -

Sep 13, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Familial cancer of breast

Uncertain:2

Aug 30, 2019

Division of Medical Genetics, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8071C>T variant has been reported in individuals with breast cancer [PMID: 12935922, 20305132, 19781682 ] and also in individuals with no history of cancer [PMID: 24728327, 19781682]. The c.8071C>T variant has an allele frequency of 0.0001353 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. -

Feb 09, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Mar 17, 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.8071C>T (p.Arg2691Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of 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 0.00014 in 258358 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.8071C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer, chronic lymphocytic leukemia, thyroid cancer, colorectal cancer, prostate cancer and lung cancer (Kwong_2020, Li_2020, Adedokun_2019, Wei_2019, Hauke_2018, Xie_2018, Yurgelun_2017, Lu_2015, Yu_2015, Guarini_2012, Bernstein_2010, Tavtigian_2009, Heikkinen_2005, Sommer_2003). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One co-occurrence with another pathogenic variant has been reported internally (PALB2 c.1451T>A, p.Leu484X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ovarian cancer

Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Apr 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 20, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with a personal history of breast or other cancers, but also identified in unaffected controls (PMID: 20305132, 12935922, 21993670, 15756685, 19781682, 24728327, 28580595, 26530882, 28135145, 29522266, 30197789, 34326862, 28652578, 32068069, 26689913); 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: 25563586, 24728327, 30197789, 29731985, 29134647, 12935922, 23633543, 28580595, 26530882, 19781682, 31871109, 15756685, 28135145, 21993670, 29522266, 29880898, 30311369, 33471991, 32107087, 32068069, 28652578, 26689913, 31248605, 20305132, 35406568, 31742824, 36353970, 36818616, 34326862, 36387164, 35585550) -

Familial colorectal cancer type X

Uncertain:1

Apr 11, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;.

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

2.0

M;M

PhyloP100

5.7

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.84

Gain of catalytic residue at L2692 (P = 0.0154);Gain of catalytic residue at L2692 (P = 0.0154);

MVP

0.89

MPC

0.42

ClinPred

0.27

GERP RS

5.7

Varity_R

0.21

gMVP

0.54

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over