rs201199629

Variant names:

• chr11-108365423-G-A
• rs201199629
• NM_000051.4:c.9086G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108365423-G-A
• chr11-108365423-G-C
• chr11-108365423-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:20 B:4 O:1
• Conservation: PhyloP100: 4.45

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]

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]

ACMG classification

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: {Likely_benign=3, Benign=1, Uncertain_significance=16, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.9086G>A	p.Gly3029Asp	missense_variant	Exon 63 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.9086G>A	p.Gly3029Asp	missense_variant	Exon 63 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152178 Hom.: 0 Cov.: 32

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: 32 AN: 251462 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135904

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.: 0 Cov.: 31 AF XY: 0.000413 AC XY: 300 AN XY: 727242

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: 23 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74332

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.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:20 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:8

Mar 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); Reported in individuals with breast, ovarian, colorectal, pancreatic, and other cancers, but also observed in control subjects (PMID: 19781682, 26689913, 28779002, 27978560, 28652578, 28135145, 28726808, 29522266, 29684080, 33134171, 35264596, 35534704, 32885271, 25186627, 20305132, 34326862, 35047863); In silico analysis indicates 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, 32885271, 20305132, 35534704, 34326862, 25186627, 23532176, Kamgar[CaseReport]2023, 23555315) -

Feb 18, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:4 Benign:1

Jul 05, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2021

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.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:2 Benign:1

Nov 29, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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’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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia, 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, de Oliveira_2022, Guindalini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 33134171, 35264596, 26917275, 26689913, 27978560, 19781682, 25186627, 26787654, 28135145, 35534704). ClinVar contains an entry for this variant (Variation ID: 127468). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Feb 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 23, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 12, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1 Benign:1

Mar 07, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 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]. -

Breast and/or ovarian cancer Uncertain:1

Apr 05, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder Uncertain:1

Oct 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Aug 01, 2020

Molecular Oncology Research Center, Barretos Cancer Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.078	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;.
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.98	L;L
PrimateAI	Pathogenic	0.84	D
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	T
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

Other links and lift over

dbSNP: rs201199629; hg19: chr11-108236150; COSMIC: COSV104592036; COSMIC: COSV104592036;