rs587782195

Variant names:

• chr11-108282822-A-G
• rs587782195
• NM_000051.4:c.3689A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108282822-A-G
• chr11-108282822-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000051.4(ATM):​c.3689A>G​(p.Asn1230Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,551,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1230I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:3
• Conservation: PhyloP100: 0.456
• Publications: 5 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 42 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.035779506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.3689A>G	p.Asn1230Ser	missense_variant	Exon 25 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3689A>G	p.Asn1230Ser	missense_variant	Exon 25 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249282 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 45 AN: 1398970 Hom.: 0 Cov.: 27 AF XY: 0.0000429 AC XY: 30 AN XY: 699224

African (AFR) AF: 0.00 AC: 0 AN: 31880

American (AMR) AF: 0.0000227 AC: 1 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25668

East Asian (EAS) AF: 0.00 AC: 0 AN: 39270

South Asian (SAS) AF: 0.00 AC: 0 AN: 84472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.0000407 AC: 43 AN: 1056506

Other (OTH) AF: 0.0000172 AC: 1 AN: 58284

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.0000882 AC: 6 AN: 68046

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

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Jul 12, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, but also in unaffected controls (Decker et al., 2017; Hauke et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 28779002, 29522266, 19781682, 33471991) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2015

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: The c.3689A>G in ATM gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant of interest was not found in control population of ExAC. The variant of interest has been reported as VUS by several independent reputable database/clinical laboratories. More definitive data are needed. Taking together, the variant was classified as VUS until more information becomes available. -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM2, BP4 -

Ataxia-telangiectasia syndrome Uncertain:3

Sep 16, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.3689A>G (p.Asn1230Ser) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Jan 21, 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 serine, which is neutral and polar, at codon 1230 of the ATM protein (p.Asn1230Ser). This variant is present in population databases (rs587782195, gnomAD 0.003%). 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: 142043). 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. -

Apr 21, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:2 Benign:1

May 15, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Mar 26, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.3689A>G (p.Asn1230Ser) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Apr 25, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 16, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Jan 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Asn1230Ser variant was identified in 4 of 37352 proband chromosomes (frequency: 0.0001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 10976 control chromosomes from healthy individuals (Decker 2017, Hauke 2018). The variant was also identified in dbSNP (ID: rs587782195) as “With Uncertain significance allele”, and in ClinVar (as likely benign by Ambry Genetics and uncertain significance by GeneDx, Invitae, and Integrated Genetics). The variant was not identified in COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 4 of 275282 chromosomes at a frequency of 0.000015 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34010 chromosomes (freq: 0.000029), and European (Non-Finnish) in 3 of 125972 chromosomes (freq: 0.000024); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn1230 residue is not conserved in mammals and the variant amino acid Serine (Ser) is present in mouse, pig, chicken, and African clawed frog, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.1
DANN	Benign	0.22
DEOGEN2	Benign	0.041	.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.67	T;T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	.;N;N
PhyloP100		0.46
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.26	N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.12, 0.090
MVP		0.64
MPC		0.097
ClinPred		0.012	T
GERP RS		2.3
Varity_R		0.056
gMVP		0.049
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs587782195; hg19: chr11-108153549;