ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9086G>A (p.Gly3029Asp) (rs201199629)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115274 SCV000183889 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115274 SCV000902677 benign Hereditary cancer-predisposing syndrome 2015-11-12 criteria provided, single submitter clinical testing
Counsyl RCV000198158 SCV000799771 uncertain significance Ataxia-telangiectasia syndrome 2018-05-04 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000780893 SCV000918525 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The c.9086G>A (p.Gly3029Asp) in ATM gene is a missense variant involves a mildly conserved nucleotide located within the FATC domain that plays a role in redox-dependent structural and cellular stability. The 4/4 in silico tools predict deleterious outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.9086G>A is present in the control population dataset of gnomAD at a low frequency of 0.0001 (39/277226 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0039, suggesting that it is not a common polymorphism. The variant has not, to our knowledge, been reported in AT patients, but was identified in multiple individuals presented with BrC, OvC and CRC cancers without strong evidence for causality. The variant was also identified in healthy controls (Tavtigian_2009). Several clinical laboratories cite the variant as VUS. Taken together, due to the lack of supportive evidence, the variant was classified as VUS, until new information becomes available.
Invitae RCV000198158 SCV000254161 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 3029 of the ATM protein (p.Gly3029Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs201199629, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer, and in two unaffected individuals from a case-control study (PMID: 19781682), as well as in an individual with ovarian cancer (PMID: 26689913) and in individuals with colorectal cancer (PMID: 27978560, 28135145). ClinVar contains an entry for this variant (Variation ID: 127468). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000198158 SCV000838624 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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