ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.9086G>A (p.Gly3029Asp) (rs201199629)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212098 SCV000149183 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.9086G>A at the cDNA level, p.Gly3029Asp (G3029D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has been reported in individuals with breast, ovarian, colorectal, and pancreatic cancer, but has also been observed in control subjects (Tavtigian 2009, Lu 2015, Pearlman 2017, Decker 2017, Tiao 2017, Yurgelun 2017, Chaffee 2018, Hauke 2018, Yehia 2018). This variant was reported in a multi-ethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Gly3029Asp was observed at an allele frequency of 0.028% (35/126,712) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the FATC domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Gly3029Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 Health, Inc 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 2021-06-05 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=7). 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 re-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 and 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 Clinical Genomics Lab, 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.

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