11-108293374-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):c.4673C>T(p.Thr1558Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,600,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 2.11

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11133984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.4673C>T	p.Thr1558Met	missense_variant	Exon 31 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.4673C>T	p.Thr1558Met	missense_variant	Exon 31 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250606

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135468

show subpopulations

Gnomad AFR exome

AF:

0.000246

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1448016

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

721194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000191

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1558M variant (also known as c.4673C>T), located in coding exon 30 of the ATM gene, results from a C to T substitution at nucleotide position 4673. The threonine at codon 1558 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in individuals from cancer cohorts and in unaffected control populations in several case-control studies (Tiao G et al. Leukemia, 2017 Oct;31:2244-2247; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Dorling et al. N Engl J Med 2021 02;384:428-439; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration was also reported along with another ATM missense alteration in a patient with ataxia telangiectasia (Woelke S et al. Front Immunol 2018 Sep;9:2000). This amino acid position is not well conserved in available vertebrate species. 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. -

Oct 30, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 c.4673C>T located in exon 31 of the ATM gene, is predicted to result in the substitution of threonine by methionine at codon 1558, p.(Thr1558Met). This variant is found in 3/14886 at a filter allele frequency of 0.005% in the gnomAD v2.1.1 database (African non-cancer data set). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.068) suggests that it does not affect the protein function (BP4). To our knowledge, functional studies have not been reported for this variant. In addition, the variant was also identified in the ClinVar database (10x uncertain significance) and in LOVD database (1x uncertain significance, 2x not classified). Based on currently available information, the variant c.4673C>T is classified as an uncertain significance variant according to ClinGen-ATM Guidelines version v1.1. -

Nov 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1558 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In prostate and breast cancer case-control studies, this variant has been observed in affected and unaffected individuals (PMID: 30287823, 33436325, 33471991). In a biliary tract cancer case-control study, the variant was not observed in affected cases and present in the control group (PMID: 36243179). This variant has been observed in an individual affected with gastric cancer who has a family history of gastric cancer (PMID: 34326862). This variant has been identified in 6/281966 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. -

Ataxia-telangiectasia syndrome

Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1558 of the ATM protein (p.Thr1558Met). This variant is present in population databases (rs587781712, gnomAD 0.02%). This missense change has been observed in individual(s) with gastric cancer, melanoma, and/or prostate cancer (PMID: 33436325, 34262154, 34326862). ClinVar contains an entry for this variant (Variation ID: 141389). 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%. 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. -

not specified

Uncertain:1

Sep 27, 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.4673C>T (p.Thr1558Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250606 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4673C>T has been reported, in case-control studies or in case reports, in individuals affected with Ataxia-Telangiectasia and various types of cancers including Breast cancer, Gastric cancer, biliary tract cancer, and prostate cancer (example, Karlsson_2021, Momozawa_2018, Tiao_2017, Woelke_2018, Dorling_2021, Bhai_2021, Okawa_2023), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33436325, 30287823, 28652578, 30279689, 33471991, 34326862, 36243179). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder

Uncertain:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.4673C>T variant is predicted to result in the amino acid substitution p.Thr1558Met. This variant has been reported in an individual with prostate cancer and interpreted as uncertain significance (Karlsson et al. 2021. PubMed ID: 33436325, Table S4). It has also been reported in controls from a breast cancer cohort study (Momozawa et al. 2018. PubMed ID: 30287823, Table S1). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141389/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Apr 25, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a second ATM variant in an individual with ataxia-telangiectasia (Woelke et al., 2018); This variant is associated with the following publications: (PMID: 26022708, 30287823, 28652578, 30279689, 33436325) -

Diffuse midline glioma, H3 K27-altered

Uncertain:1

Aug 05, 2021

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial cancer of breast

Uncertain:1

Feb 25, 2024

Baylor Genetics

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

0.089

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.097

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.076

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

T;.

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.77

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.068

Sift

Benign

0.088

T;T

Sift4G

Benign

0.094

T;T

Polyphen

0.021

B;B

Vest4

0.16

MutPred

0.42

Gain of methylation at K1560 (P = 0.0738);Gain of methylation at K1560 (P = 0.0738);

MVP

0.91

MPC

0.13

ClinPred

0.16

GERP RS

4.4

Varity_R

0.077

gMVP

0.38

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

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