rs758962678

Positions:

Variant summary

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

The NM_000051.4(ATM):c.241A>G(p.Asn81Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,572 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 6.94

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=0.14885944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.241A>G	p.Asn81Asp	missense_variant	4/63	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.241A>G	p.Asn81Asp	missense_variant	4/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

250838

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000551

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461348

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000447

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant was found in a cell line and showed impaired ATM activity and reduced p53 binding, but it is unclear how this may affect disease. (PMID: 15713674) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 05, 2023	The frequency of this variant in the general population, 0.00055 (19/34506 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer and in a control individual (PMID: 31206626 (2019)), also in individuals with suspected hereditary cancer or breast/ovarian cancer (PMIDs: 30262796 (2018), 27720647 (2015)). Additionally, this variant was assessed in a functional study, however, the results do not conclusively indicate a pathogenic role for this variant (PMID: 15713674 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast cancer (Quezada Urban 2018, Weitzel 2019); This variant is associated with the following publications: (PMID: 27720647, 31658756, 31206626, 30262796, 15713674) -

Ataxia-telangiectasia syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 81 of the ATM protein (p.Asn81Asp). This variant is present in population databases (rs758962678, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 30262796, 31206626). ClinVar contains an entry for this variant (Variation ID: 187119). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 06, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 05, 2022	The p.N81D variant (also known as c.241A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 241. The asparagine at codon 81 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10). This alteration was also detected in a study of 1054 BRCA-mutation-negative Hispanic women with hereditary breast cancer and 312 local and 887 multi-ethnic controls (Weitzel JN et al. Cancer, 2019 08;125:2829-2836). Experiments conducted in fibroblast and lymphoblast cells indicate that an ATM construct containing four missense alterations, including N81D, maintained kinase activity and the ability to bind p53 (Fernandes N et al. J. Biol. Chem. 2005 Apr;280:15158-64). This amino acid position is 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2021	This missense variant replaces asparagine with aspartic acid at codon 81 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. However, an ATM variant protein containing four missense mutations between codons 81 to 87, including p.Asn81Asp, has been shown to be similar to wild-type in kinase and p53 binding assays and survival after ionizing radiation exposure (PMID: 15713674). This variant has been observed in individuals suspected of hereditary breast and ovarian cancer (PMID: 30262796) and hereditary cancer (PMID: 27720647). This variant has been identified in 19/250838 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

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 20, 2021

Variant summary: ATM c.241A>G (p.Asn81Asp) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of 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 7.6e-05 in 250838 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.241A>G has been reported in the literature in individuals affected with breast cancer or other cancer (e.g. Mu_2016, QuezadaUrban_2018, Weitzel_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.068

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.13

Sift

Benign

0.13

T;T;T;D;.;T;.;.;.;.;.

Sift4G

Uncertain

0.031

D;T;T;T;T;T;.;.;.;T;T

Polyphen

0.38, 0.83

.;B;.;.;.;B;P;P;P;P;.

Vest4

0.49, 0.46, 0.52, 0.47

MutPred

0.14

Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);Loss of MoRF binding (P = 0.0457);

MVP

0.86

MPC

0.39

ClinPred

0.18

GERP RS

6.1

Varity_R

0.25

gMVP

0.15

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