rs77208665

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001184.4(ATR):c.2290A>G(p.Lys764Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00459 in 1,612,994 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K764K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 30 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 4.14

Publications

16 publications found

Variant links:

COSMIC-nc: COSV63389180

Genes affected

ATR (HGNC:882): (ATR serine/threonine kinase) The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1. [provided by RefSeq, Aug 2017]

ATR Gene-Disease associations (from GenCC):

Seckel syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
familial prostate carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009344518).

BP6

Variant 3-142555928-T-C is Benign according to our data. Variant chr3-142555928-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157970.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.2290A>G	p.Lys764Glu	missense_variant	Exon 10 of 47	ENST00000350721.9	NP_001175.2	Q13535-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 link	c.2290A>G	p.Lys764Glu	missense_variant	Exon 10 of 47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00507

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00329

AC:

823

AN:

250116

AF XY:

0.00317

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00253

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00410

GnomAD4 exome

AF:

0.00472

AC:

6889

AN:

1460704

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

3233

AN XY:

726554

show subpopulations

African (AFR)

AF:

0.000599

AC:

AN:

33384

American (AMR)

AF:

0.00234

AC:

104

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00670

AC:

175

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000769

AC:

AN:

85800

European-Finnish (FIN)

AF:

0.00210

AC:

112

AN:

53410

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00542

AC:

6021

AN:

1111706

Other (OTH)

AF:

0.00618

AC:

373

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

369

738

1106

1475

1844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.00337

AC:

513

AN:

152290

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41566

American (AMR)

AF:

0.00608

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00507

AC:

345

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00449

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00325

AC:

395

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00567

EpiControl

AF:

0.00551

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATR p.Lys764Glu variant was identified in 1 of 100 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and was not identified in 72 control chromosomes from healthy individuals (Durocher_2006_17010193). In Wang et al., the variant was also identified in 1/48 breast cancer tumours (Wang_2008_PMID: 18281469). The variant was also identified in the following databases: dbSNP (ID: rs77208665) and was found in ClinVar (where it was reported as likely benign and a VUS for Seckel syndrome 1), Clinvitae, Cosmic (with a FATHMM prediction of Pathogenic (score=0.95)), MutDB and LOVD 3.0. The variant was identified in control databases in 902 of 281492 chromosomes (5 homozygous) at a frequency of 0.003204 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 64 of 10326 chromosomes (freq: 0.006198), European (non-Finnish) in 630 of 128766 chromosomes (freq: 0.004893), other in 26 of 7180 chromosomes (freq: 0.003621), Latino in 89 of 35200 chromosomes (freq: 0.002528), European (Finnish) in 53 of 25088 chromosomes (freq: 0.002113), South Asian in 26 of 30084 chromosomes (freq: 0.000864) and African in 14 of 24956 chromosomes (freq: 0.000561); it was not observed in the East Asian populations. The p.Lys764 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. -

Jan 20, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATR: BP4, BS2 -

Oct 14, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28787443) -

Seckel syndrome 1

Uncertain:1Benign:1

Nov 14, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Benign

-0.031

Eigen_PC

Benign

0.0053

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0093

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

4.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Benign

0.042

Sift4G

Uncertain

0.021

Polyphen

0.92

Vest4

0.62

MVP

0.79

MPC

0.53

ClinPred

0.011

GERP RS

4.2

Varity_R

0.36

gMVP

0.34

Mutation Taster

=98/2

polymorphism

(source)

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

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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