ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.322G>A (p.Gly108Ser) (rs587782461)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131548 SCV000186548 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000131548 SCV000292181 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing
Invitae RCV000458425 SCV000545296 uncertain significance Li-Fraumeni syndrome 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 108 of the TP53 protein (p.Gly108Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs587782461, ExAC 0.01%). This variant has been reported in an individual affected with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 142431). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.
GeneDx RCV000679368 SCV000567174 uncertain significance not provided 2016-09-28 criteria provided, single submitter clinical testing This variant is denoted TP53 c.322G>A at the cDNA level, p.Gly108Ser (G108S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). Although this variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a polymorphism, it has been observed as a somatic variant in a variety of tumor tissues (Strauss 2016, Harvey 2016, Sakuragi 2001, COSMIC). This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly108Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Gly108Ser occurs at a position that is not conserved across species and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Gly108Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000679368 SCV000806237 uncertain significance not provided 2018-01-05 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030738 SCV001193754 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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