rs201199629

chr11-108365423-G-Achr11-108365423-G-Cchr11-108365423-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):c.9086G>A(p.Gly3029Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00039 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. G3029R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20B:3O:1

Conservation

PhyloP100: 4.45

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 made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21475926).

BP6

Variant 11-108365423-G-A is Benign according to our data. Variant chr11-108365423-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127468.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=17, Benign=1, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.9086G>A	p.Gly3029Asp	missense_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.9086G>A	p.Gly3029Asp	missense_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251462

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000415

AC:

607

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000528

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000151

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000303

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:8

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2023	Reported in individuals with breast, ovarian, colorectal, and pancreatic cancer, but also observed in control subjects (PMID: 19781682, 26689913, 28779002, 27978560, 28652578, 28135145, 28726808, 29522266, 29684080, 33134171, 35264596); Reported in a multi-ethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (PMID: 23555315); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 21787400, 26689913, 26787654, 27978560, 28779002, 28135145, 28726808, 26917275, 29522266, 29684080, 28652578, 25759019, 33134171, 35047863, 35264596, 34326862, 32885271, 20305132, 25186627, 23532176, 23555315) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 10, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 18, 2019	The frequency of this variant in the general population, 0.00025 (32/129180 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant been reported in individuals affected with breast cancer, colorectal cancer, ovarian cancer, and pancreatic cancer, as well as in unaffected control individuals (PMID: 33134171 (2020), 28726808 (2018), 29684080 (2018), 28779002 (2017), 28135145 (2017), 27978560 (2016), 26689913 (2015), 23555315 (2013), 19781682 (2009)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is unknown or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Ataxia-telangiectasia syndrome

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 05, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 13, 2021	The ATM c.9086G>A (p.Gly3029Asp) missense change has a maximum frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-108236150-G-A?dataset=gnomad_r2_1). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with cancer including breast cancer, ovarian cancer, colorectal cancer, and rectal cancer (PS4; PMID: 19781682, 27978560, 28135145, 26689913, 23555315, 21787400). This variant is present 10x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2; https://whi.color.com/). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS4, BS2, BP4. -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2021	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.9086G>A, in exon 63 that results in an amino acid change, p.Gly3029Asp. This sequence change has been described in the gnomAD database with a frequency of 0.025% in the non-Finnish European subpopulation (dbSNP rs201199629). The p.Gly3029Asp change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly3029Asp substitution. This sequence change has previously been identified in individuals with breast and other cancers, as well as in populations of healthy controls (PMID: 19781682, 28779002, 29522266, 27978560, 33134171, 28135145, 28726808, Flossies√¢‚Ç¨‚Ñ¢s database https://whi.color.com/gene/ENSG00000149311). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Gly3029Asp change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2022	Variant summary: ATM c.9086G>A (p.Gly3029Asp) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 256260 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00013 vs 0.004), allowing no conclusion about variant significance. However, this variant has also been reported in 2/2559 African American women and 8/7325 European American women (i.e. with an allele frequency of 0.001012 in 9884 subjects) who were older than age 70 and cancer free (FLOSSIES database), supporting a benign role for the variant. c.9086G>A has been reported in the literature as a VUS in individuals undergoing multigene panel testing for a variety of cancer types and has recently been reported to not segregate with disease in at-least one family with a history of breast/colorectal cancer (example, Bernstein_2010, Lu_2015, Pearlman_2016, Tavtigian_2009, Tung_2015, Yurgelun_2017, Jesinghaus_2016, Grasel_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/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. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=10). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of conclusive evidence supporting an actionable outcome as outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 12, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 2023	The p.G3029D variant (also known as c.9086G>A), located in coding exon 62 of the ATM gene, results from a G to A substitution at nucleotide position 9086. The glycine at codon 3029 is replaced by aspartic acid, an amino acid with similar properties. This variant has been identified in numerous disease cohorts as well as unaffected control groups across studies (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker BJ et al. Med. Genet. 2017 Nov;54(11):732-741; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-71; Chaffee KG et al. Genet. Med. 2018 01;20(1):119-127; Hauke J et al. Cancer Med. 2018 Apr;7(4):1349-1358; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 05, 2023

- -

ATM-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2023

The ATM c.9086G>A variant is predicted to result in the amino acid substitution p.Gly3029Asp. This variant has been reported in individuals with a history of breast, ovarian, and colorectal cancers (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Supplementary Data 12, Lu et al. 2015. PubMed ID: 26689913; eTable 2, Pearlman et al. 2017. PubMed ID: 27978560; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145), but has also been identified in control cohorts (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108236150-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127468/). 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

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Mar 07, 2022

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Molecular Oncology Research Center, Barretos Cancer Hospital

Aug 01, 2020

- -

Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Likely benign and reported on 10-21-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.078

T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

T;.

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.98

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.011

B;B

Vest4

0.25

MVP

0.81

MPC

0.17

ClinPred

0.11

GERP RS

4.2

Varity_R

0.59

gMVP

0.66

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over