ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.469G>A (p.Val157Ile) (rs121912654)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164816 SCV000215499 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235399 SCV000293287 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.469G>A at the cDNA level, p.Val157Ile (V157I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has been identified in individuals with sarcoma, early-onset breast cancer, and in a bone marrow sample from an individual with acute myeloid leukemia, as well as having been observed as a somatic variant in several different tumor types (Mitchell 2013, Forbes 2014, Hou 2015, Jalkh 2017). 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 Val157Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). 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 TP53 Val157Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000528459 SCV000629823 uncertain significance Li-Fraumeni syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 157 of the TP53 protein (p.Val157Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs121912654, ExAC 0.03%). This variant has been reported in individuals with sarcoma and breast cancer (PMID: 23894400, 28202063). ClinVar contains an entry for this variant (Variation ID: 185404). 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.
Color RCV000164816 SCV000911006 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing

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