11-108293319-G-T

Variant names:

Variant summary

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

The NM_000051.4(ATM):c.4618G>T(p.Asp1540Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,383,310 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1540H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.945

Publications

4 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 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.4618G>T	p.Asp1540Tyr	missense_variant	Exon 31 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.4618G>T	p.Asp1540Tyr	missense_variant	Exon 31 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

230222

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000506

AC:

AN:

1383310

Hom.:

Cov.:

AF XY:

0.00000870

AC XY:

AN XY:

689414

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31108

American (AMR)

AF:

0.00

AC:

AN:

40268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24918

East Asian (EAS)

AF:

0.00

AC:

AN:

38994

South Asian (SAS)

AF:

0.0000878

AC:

AN:

79752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5184

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053248

Other (OTH)

AF:

0.00

AC:

AN:

57492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:2

Oct 28, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1540 of the ATM protein (p.Asp1540Tyr). This variant is present in population databases (rs778622948, gnomAD 0.01%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 35171259). ClinVar contains an entry for this variant (Variation ID: 524281). 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) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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:1

Oct 12, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D1540Y variant (also known as c.4618G>T), located in coding exon 30 of the ATM gene, results from a G to T substitution at nucleotide position 4618. The aspartic acid at codon 1540 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

D;.

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

0.94

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.2

D;D

REVEL

Benign

0.26

Sift

Benign

0.030

D;D

Sift4G

Benign

0.082

T;T

Polyphen

0.96

D;D

Vest4

0.61

MutPred

0.40

Gain of methylation at K1536 (P = 0.0994);Gain of methylation at K1536 (P = 0.0994);

MVP

0.79

MPC

0.35

ClinPred

0.91

GERP RS

4.4

Varity_R

0.18

gMVP

0.53

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over