NM_000051.4:c.3577G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000051.4(ATM):c.3577G>A(p.Val1193Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000089 in 1,460,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V1193A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

Splicing: ADA: 0.8681

Clinical Significance

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

Conservation

PhyloP100: 6.75

Publications

4 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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 34 uncertain in NM_000051.4

BP4

Computational evidence support a benign effect (MetaRNN=0.21171507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.3577G>A	p.Val1193Ile	missense_variant, splice_region_variant	Exon 25 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.3577G>A	p.Val1193Ile	missense_variant, splice_region_variant	Exon 25 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250518

AF XY:

0.0000148

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460584

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726572

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.00

AC:

AN:

86040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111482

Other (OTH)

AF:

0.00

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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

Cov.:

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 13, 2017

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.3577G>A (p.Val1193Ile) variant involves the alteration of a conserved nucleotide located in the first nucleotide of exon 25 in the ATM gene. The variant lies within the Armadillo-like helical domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant may introduce an SF2/ASF ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120766 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories have classified this variant as being of uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

May 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with a personal and family history of pancreatic cancer who also harbored a pathogenic PALB2 variant (PMID: 35135108); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28652578, 19781682, 34326862, 35135108) -

Feb 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Jan 16, 2018

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V1193I variant (also known as c.3577G>A) is located in coding exon 24 of the ATM gene. The valine at codon 1193 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 24. This amino acid position is highly 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. -

Nov 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with isoleucine at codon 1193 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/250518 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. -

Ataxia-telangiectasia syndrome

Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1193 of the ATM protein (p.Val1193Ile). This variant is present in population databases (rs779148780, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 186973). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

May 11, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATM-related disorder

Uncertain:1

Nov 03, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.3577G>A variant is predicted to result in the amino acid substitution p.Val1193Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108153437-G-A). This variant has been interpreted in ClinVar as uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/186973/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

.;T;T

Eigen

Benign

0.092

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

T;T;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.2

.;M;M

PhyloP100

6.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.036

D;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.45

.;B;B

Vest4

0.24, 0.26

MVP

0.81

MPC

0.13

ClinPred

0.31

GERP RS

5.4

Varity_R

0.077

gMVP

0.28

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Benign

0.63

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over