Variant rs587779858 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000051.4(ATM):c.68G>A(p.Arg23Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,418 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: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.67

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 -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4027972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.68G>A	p.Arg23Gln	missense_variant	2/63	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.68G>A	p.Arg23Gln	missense_variant	2/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461418

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727032

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:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

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

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 31, 2023	This missense variant replaces arginine with glutamine at codon 23 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported together with another ATM missense variant (p.Gly2020Asp) in an individual affected with atypical ataxia telangiectasia (PMID: 31050087). Cells derived from this individual had normal ATM protein levels and CHK2 phosphorylation and decreased KAP1 phosphorylation (PMID: 31050087). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 30303537, 33471991) and in a healthy control (PMID: 33471991). This variant has not been identified 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2023	The p.R23Q variant (also known as c.68G>A), located in coding exon 1 of the ATM gene, results from a G to A substitution at nucleotide position 68. This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was also identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This alteration has also been reported in a patient with atypical features of ataxia-telangiectasia, in conjunction with another missense alteration; both ATM variants were classified as uncertain significance by study authors (Fiévet A et al. Hum Mutat, 2019 10;40:1713-1730). The arginine at codon 23 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2024	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; Identified with another ATM variant in a patient with atypical ataxia-telangiectasia (PMID: 31050087); Observed in individuals with breast or gastric cancer (PMID: 25186627, 30303537, 33525650); This variant is associated with the following publications: (PMID: 30303537, 17344846, 28873162, 25186627, 31050087, 33525650) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2021	- -

Ataxia-telangiectasia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 23 of the ATM protein (p.Arg23Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal/family history of breast/ovarian cancer and clinical features of ataxia-telangiectasia (PMID: 30303537, 31050087, 32068069). ClinVar contains an entry for this variant (Variation ID: 127429). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 01, 2021

- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

The ATM c.68G>A variant is predicted to result in the amino acid substitution p.Arg23Gln. This variant has been reported in an individual with colorectal adenocarcinoma (Table S2 in Greenman et al. 2007. PubMed ID: 17344846), in five individuals with breast cancer and in one case control (Table s1 in Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991; Table S1 in Kwong et al 2020. PubMed ID: 32068069; Table S3 in Girard et al. 2019. PubMed ID: 30303537; Table S1 in Tung et al 2014. PubMed ID: 25186627), in an individual with gastric cancer (Table S1 in Herrera-Pariente et al. 2021. PubMed ID: 33525650), and in an individual with ataxia-telangiectasia who also harbored a second variant in ATM (Figure 2b in Fiévet et al. 2019. PubMed ID: 31050087). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/127429/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.40

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

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

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

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0, 0.45

.;D;.;.;.;D;B;B;B;B;.

Vest4

0.87, 0.85, 0.58, 0.89

MutPred

0.24

Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);

MVP

0.90

MPC

0.60

ClinPred

1.0

GERP RS

4.4

Varity_R

0.39

gMVP

0.74

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

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

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