Submissions for variant NM_000546.6(TP53):c.1010G>C (p.Arg337Pro)

dbSNP: rs121912664

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187412	SCV001354217	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 337 in the tetramerization domain 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 the mutant protein to be defective in tetramer formation (PMID: 19454241, 20978130, 29955864) and transactivation function (PMID: 10519380, 10719737, 12826609, 19454241, 29955864). This variant has been reported in three individuals affected with Li-Fraumeni syndrome (PMID: 2042652, 29955864). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same amino acid position, p.Arg337His, is known to be disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV000154527	SCV001577877	likely pathogenic	Li-Fraumeni syndrome	2021-04-23	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10864200, 16033918, 16494995, 21192060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609, 19454241, 29955864). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 20426520). ClinVar contains an entry for this variant (Variation ID: 177879). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 337 of the TP53 protein (p.Arg337Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.
Genome-Nilou Lab	RCV001187412	SCV002582332	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288666	SCV002582994	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001187412	SCV002610440	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-28	criteria provided, single submitter	clinical testing	The p.R337P variant (also known as c.1010G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1010. The arginine at codon 337 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in a 5 year old patient with acute lymphoblastic leukemia and adrenocortical carcinoma, as well as several family members with cancer (Karakas Z et al. Pediatr Hematol Oncol, 2010 May;27:297-305). This variant is in the oligomerization domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays, and loss of tetramer formation in studies conducted in human cell lines (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Fischer NW et al. J. Natl. Cancer Inst., 2018 12;110:1418-1421). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154527	SCV000204199	likely pathogenic	Li-Fraumeni syndrome	2009-08-13	no assertion criteria provided	clinical testing