Submissions for variant NM_000051.4(ATM):c.9086G>A (p.Gly3029Asp)

gnomAD frequency: 0.00016  dbSNP: rs201199629

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212098	SCV000149183	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	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)
Ambry Genetics	RCV000115274	SCV000183889	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198158	SCV000254161	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000198158	SCV000799771	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000198158	SCV000838624	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115274	SCV000902677	benign	Hereditary cancer-predisposing syndrome	2015-11-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780893	SCV000918525	likely benign	not specified	2022-07-31	criteria provided, single submitter	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 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.
Athena Diagnostics	RCV000212098	SCV001143129	uncertain significance	not provided	2019-02-18	criteria provided, single submitter	clinical testing
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001374551	SCV001438678	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-08-01	criteria provided, single submitter	research
Baylor Genetics	RCV000198158	SCV001481716	uncertain significance	Ataxia-telangiectasia syndrome	2019-07-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000198158	SCV001737468	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-13	criteria provided, single submitter	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.
Genetic Services Laboratory, University of Chicago	RCV000780893	SCV002065558	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	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.
Sema4, Sema4	RCV000115274	SCV002530736	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288591	SCV002581542	uncertain significance	Familial cancer of breast	2022-03-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780893	SCV004024618	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212098	SCV004184193	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212098	SCV004222307	uncertain significance	not provided	2019-02-18	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212098	SCV004226245	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492468	SCV004240023	uncertain significance	Breast and/or ovarian cancer	2023-04-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288591	SCV005084072	likely benign	Familial cancer of breast	2024-06-24	criteria provided, single submitter	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].
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212098	SCV001740035	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535462	SCV001749382	not provided	Ataxia-telangiectasia syndrome; Malignant tumor of breast		no assertion provided	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212098	SCV001953616	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212098	SCV001967525	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549574	SCV004727442	uncertain significance	ATM-related disorder	2023-10-30	no assertion criteria provided	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.