ClinVar Miner

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

gnomAD frequency: 0.00016  dbSNP: rs201199629
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212098 SCV000149183 uncertain significance not provided 2022-10-12 criteria provided, single submitter clinical testing Reported in individuals with breast, ovarian, colorectal, and pancreatic cancer, but also observed in control subjects (Tavtigian et al., 2009; Lu et al., 2015; Decker et al., 2017; Pearlman et al., 2017; Tiao et al., 2017; Yurgelun et al., 2017; Chaffee et al., 2018; Hauke et al., 2018; Yehia et al., 2018; Grasel et al., 2020); Reported in a multi-ethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman et al., 2013); 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, 23555315, 23532176, 35047863)
Ambry Genetics RCV000115274 SCV000183889 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-02 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 alteration has been detected in both breast cancer patients and healthy control individuals across numerous 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; Hauke J et al. Cancer Med. 2018 Apr;7(4):1349-1358). It was also reported in 1/450 probands with early onset colorectal cancer and was reported in a cohort of 1058 unselected colorectal cancer patients undergoing multi-gene panel testing (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-71; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). In addition, this alteration was identified in one patient from a cohort of 302 pancreatic cancer patients (Chaffee KG et al. Genet. Med. 2018 01;20(1):119-127). 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.
Invitae RCV000198158 SCV000254161 likely benign Ataxia-telangiectasia syndrome 2020-12-04 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 Inc 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
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

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