chr11-108229202-A-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.210A>T(p.Lys70Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.62

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=0.24813846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.210A>T	p.Lys70Asn	missense_variant	Exon 4 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.210A>T	p.Lys70Asn	missense_variant	Exon 4 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460724

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726554

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:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:2

May 23, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 70 of the ATM protein (p.Lys70Asn). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 418022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Jan 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K70N variant (also known as c.210A>T), located in coding exon 3 of the ATM gene, results from an A to T substitution at nucleotide position 210. The lysine at codon 70 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly 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. -

Aug 31, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with asparagine at codon 70 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. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31394 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. -

not specified

Uncertain:1

Nov 06, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.210A>T at the cDNA level, p.Lys70Asn (K70N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys70Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Lys70Asn occurs at a position that is highly conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Lys70Asn is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

.;T;T;T;.;T;T;T;T;T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

D;D;D;D;D;.;.;.;.;.;D

M_CAP

Benign

0.080

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.6

.;M;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.8

D;N;D;D;.;N;.;.;.;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.0030

D;D;D;D;.;D;.;.;.;.;.

Sift4G

Uncertain

0.0050

D;D;D;D;D;D;.;.;.;D;D

Polyphen

1.0, 1.0

.;D;.;.;.;D;D;D;D;D;.

Vest4

0.78, 0.79, 0.82, 0.79

MutPred

0.28

Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);Loss of methylation at K70 (P = 0.0223);

MVP

0.83

MPC

0.63

ClinPred

0.98

GERP RS

-0.099

Varity_R

0.51

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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