Variant 11-108252019-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):c.1790C>T(p.Pro597Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.43

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.1790C>T	p.Pro597Leu	missense_variant	11/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.1790C>T	p.Pro597Leu	missense_variant	11/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249730

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135192

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459602

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 597 of the ATM protein (p.Pro597Leu). This variant is present in population databases (rs765847854, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 422797). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 08, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal and/or family history of pancreatic cancer (Chaffee et al., 2018); This variant is associated with the following publications: (PMID: 32098966, 31141692, 28726808) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

The p.P597L variant (also known as c.1790C>T), located in coding exon 10 of the ATM gene, results from a C to T substitution at nucleotide position 1790. The proline at codon 597 is replaced by leucine, an amino acid with similar properties. This alteration has been identified in an individual with pancreatic ductal adenocarcinoma (Chaffee KG et al. Genet. Med., 2018 01;20:119-127). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.12

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;D;.

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.5

.;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.25

Sift

Benign

0.087

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.78

.;P;P

Vest4

0.82, 0.80

MutPred

0.47

Loss of catalytic residue at P596 (P = 0.0135);Loss of catalytic residue at P596 (P = 0.0135);Loss of catalytic residue at P596 (P = 0.0135);

MVP

0.87

MPC

0.36

ClinPred

0.87

GERP RS

6.0

Varity_R

0.44

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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