Submissions for variant NM_000546.6(TP53):c.706T>A (p.Tyr236Asn)

dbSNP: rs587782289

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463978	SCV000545294	uncertain significance	Li-Fraumeni syndrome	2020-02-05	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376694). This sequence change replaces tyrosine with asparagine at codon 236 of the TP53 protein (p.Tyr236Asn). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 15580553). 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.
Ambry Genetics	RCV000566931	SCV000672389	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	clinical testing	The p.Y236N variant (also known as c.706T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 706. The tyrosine at codon 236 is replaced by asparagine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been detected in a proband meeting Chompret criteria for Li-Fraumeni syndrome (LFS) (Ambry internal data). In addition, other alterations at this codon (p.Y236H, p.Y236C, p.Y236D) have been detected in individuals with Li-Fraumeni syndrome (Rines R et al. Carcinogenesis. 1998 Jun;19(6):979-84; Ambry Internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000566931	SCV002582016	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289545	SCV002582113	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289545	SCV004931605	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].