11-108365503-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000051.4(ATM):c.9166G>T(p.Val3056Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,954 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 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. V3056M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:1

Conservation

PhyloP100: 9.52

Publications

5 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 links:

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39276886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.9166G>T	p.Val3056Leu	missense_variant	Exon 63 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.9166G>T	p.Val3056Leu	missense_variant	Exon 63 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:4

Dec 17, 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 leucine, which is neutral and non-polar, at codon 3056 of the ATM protein (p.Val3056Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer and breast and/or ovarian cancer (PMID: 28726808, 29522266, 35264596). ClinVar contains an entry for this variant (Variation ID: 181908). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2017

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. -

Feb 20, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:4

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

- -

Jan 11, 2016

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2024

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; This variant is associated with the following publications: (PMID: 29522266, 35264596, 23532176, 33471991, 28726808) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATM: PM2:Supporting, BP1 -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Apr 28, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Aug 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V3056L variant (also known as c.9166G>T), located in coding exon 62 of the ATM gene, results from a G to T substitution at nucleotide position 9166. The valine at codon 3056 is replaced by leucine, an amino acid with highly similar properties. This alteration has been detected in the germline of 1/302 pancreatic ductal adenocarcinoma patients tested with a 25-gene panel (Chaffee KG et al. Genet. Med., 2018 01;20:119-127) and in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration has also been reported in the germline of 1/516 chronic lymphocytic leukemia patients and 0/8920 ethnically matched normal population control subjects of European descent (Tiao G et al. Leukemia, 2017 10;31:2244-2247). 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. -

Dec 16, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant NM_000051.4(ATM):c.9166G>T (p.Val3056Leu) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. . The gene ATM has a low rate of benign missense variation as indicated by a high The p.Val3056Leu missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 3056 of ATM is conserved in all mammalian species. The nucleotide c.9166 in ATM is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATM-related disorder

Uncertain:1

Mar 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.9166G>T variant is predicted to result in the amino acid substitution p.Val3056Leu. This variant has been reported in an individual with pancreatic and an individual with breast and/or ovarian cancer (Table S2, Chaffee et al. 2018. PubMed ID: 28726808; Table S1, Hauke et al. 2018. PubMed ID: 29522266). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/181908/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Sep 07, 2023

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

Uncertain

0.37

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

-0.39

N;N

PhyloP100

9.5

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.040

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.26

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.94

P;P

Vest4

0.56

MutPred

0.51

Gain of stability (P = 0.0417);Gain of stability (P = 0.0417);

MVP

0.73

MPC

0.38

ClinPred

0.95

GERP RS

5.1

Varity_R

0.47

gMVP

0.70

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over