rs587778073

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000051.4(ATM):c.3630G>A(p.Met1210Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,612,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1210V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1O:1

Conservation

PhyloP100: 4.25

Publications

8 publications found

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 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

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.3630G>A	p.Met1210Ile	missense	Exon 25 of 63	NP_000042.3
	ATM	NM_001351834.2		c.3630G>A	p.Met1210Ile	missense	Exon 26 of 64	NP_001338763.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATM	ENST00000675843.1	MANE Select	c.3630G>A	p.Met1210Ile	missense	Exon 25 of 63	ENSP00000501606.1
ATM	ENST00000452508.7	TSL:1	c.3630G>A	p.Met1210Ile	missense	Exon 26 of 64	ENSP00000388058.2
ATM	ENST00000531525.3	TSL:1	c.3630G>A	p.Met1210Ile	missense	Exon 25 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251142

AF XY:

0.0000295

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1460478

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111042

Other (OTH)

AF:

0.0000166

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3

Dec 22, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1210 of the ATM protein (p.Met1210Ile). This variant is present in population databases (rs587778073, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 11996792, 19781682). ClinVar contains an entry for this variant (Variation ID: 133616). 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:3

Nov 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1210I variant (also known as c.3630G>A), located in coding exon 24 of the ATM gene, results from a G to A substitution at nucleotide position 3630. The methionine at codon 1210 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). Additionally, this variant was reported in at least one subject in a larger study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al, 2017 11;54:732-741) as well as in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al, 2018 04;7:1349-1358). This variant was also identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This alteration was detected in 1/224 unrelated Brazilian individuals with breast cancer and classified as a variant of uncertain significance by the authors (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Dec 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces methionine with isoleucine at codon 1210 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 11996792, 19781682, 28779002, 29522266, 33606809). This variant has also been identified in 6/282508 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.

Sep 07, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

not provided

Uncertain:2Benign:1

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 31, 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 (Sommer et al., 2002; Tavtigian et al., 2009; Decker et al., 2017; Hauke et al., 2018; Sandoval et al., 2021); This variant is associated with the following publications: (PMID: 11996792, 19781682, 24728327, 27153395, 29522266, 28779002, 30197789, 12935922, 35561840, 33606809)

Feb 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:2Other:1

Jan 27, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Feb 20, 2023

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.3630G>A (p.Met1210Ile) results in a conservative amino acid change in 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 2.7e-05 in 256994 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.3630G>A variant has been reported in the literature in an individual affected with Breast Cancer (Sommer 2003, Tavtigian 2009, Sandoval_2021), but also was found in healthy controls (Bodian 2014), thus these reports do not provide unequivocal conclusions about an association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

Familial cancer of breast

Uncertain:2

Feb 25, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 07, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1210 of the ATM protein (p.Met1210Ile). This variant is present in population databases (rs587778073, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 11996792, 19781682, 24728327, 27153395, 29522266, 28779002, 30197789, 12935922, 35561840, 33606809). ClinVar contains an entry for this variant (Variation ID: 133616).In silico analysis supports that this missense variant does not alter protein structure/function. 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.

Familial colorectal cancer type X

Uncertain:1

Oct 22, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.068

Eigen

Benign

-0.067

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.4

PhyloP100

4.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.66

REVEL

Benign

0.29

Sift

Benign

0.16

Sift4G

Pathogenic

0.0

Polyphen

0.091

Vest4

0.93

MutPred

0.73

Loss of catalytic residue at M1210 (P = 0.0645)

MVP

0.78

MPC

0.15

ClinPred

0.37

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.47

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over