Submissions for variant NM_000546.6(TP53):c.587G>T (p.Arg196Leu)

dbSNP: rs483352697

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001024636	SCV001186684	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-04	criteria provided, single submitter	clinical testing	The p.R196L variant (also known as c.587G>T), located in coding exon 5 of the TP53 gene, results from a G to T substitution at nucleotide position 587. The arginine at codon 196 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation two times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523825	SCV001478187	likely pathogenic	Li-Fraumeni syndrome 1	2020-12-15	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001024636	SCV001735580	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has a neutral effect on TP53 protein function (PMID: 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514536	SCV003317131	uncertain significance	Li-Fraumeni syndrome	2022-04-05	criteria provided, single submitter	clinical testing	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. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 100814). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 196 of the TP53 protein (p.Arg196Leu).
Richard Lifton Laboratory, Yale University School of Medicine	RCV000087172	SCV000120034	unknown	not provided		flagged submission	not provided	Converted during submission to Uncertain significance.
Richard Lifton Laboratory, Yale University School of Medicine	RCV000087172	SCV000155137	probable-pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.