rs758962678

Variant names:

• chr11-108229233-A-G
• rs758962678
• NM_000051.4:c.241A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108229233-A-G
• chr11-108229233-A-T

Variant summary

Our verdict is Likely benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N81S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 6.94
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14885944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.241A>G	p.Asn81Asp	missense_variant	Exon 4 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.241A>G	p.Asn81Asp	missense_variant	Exon 4 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 250838 AF XY: 0.0000516

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726944

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000447 AC: 20 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Oct 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.241A>G (p.Asn81Asp) variant has been reported in the published literature in individuals with breast cancer and in a one reportedly healthy 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)). The frequency of this variant in the general population, 0.00055 (19/34506 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. -

Jul 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal and/or family history of breast cancer (PMID: 30262796, 31206626); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27720647, 31658756, 31206626, 15713674, 30262796) -

Jun 05, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Ataxia-telangiectasia syndrome Uncertain:2

Aug 06, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 individuals 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jul 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 three BRCA1/2 negative individuals affected with breast cancer (PMID: 31206626), individuals suspected of hereditary breast and ovarian cancer (PMID: 30262796) or hereditary cancer (PMID: 27720647), as well as an unaffected control individual (PMID: 31206626). 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

Sep 20, 2021

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.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

Mar 03, 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	0.20
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
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	D
LIST_S2	Benign	0.83	T;T;T;T;T;.;.;.;.;.;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	.;M;.;.;.;M;.;.;.;.;.
PhyloP100		6.9
PrimateAI	Benign	0.36	T
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	T
GERP RS		6.1
Varity_R		0.25
gMVP		0.15
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs758962678; hg19: chr11-108099960;