Submissions for variant NM_000546.6(TP53):c.1104C>G (p.His368Gln)

dbSNP: rs1289241865

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575539	SCV000672402	likely benign	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798387	SCV000938003	uncertain significance	Li-Fraumeni syndrome	2022-02-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 368 of the TP53 protein (p.His368Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 485038). 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 not expected to disrupt TP53 protein function.
Genome-Nilou Lab	RCV002289832	SCV002582346	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000575539	SCV002583203	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004569245	SCV005054346	uncertain significance	Adrenocortical carcinoma, hereditary	2023-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575539	SCV006064396	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 368 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant behaves like wild-type in yeast transcriptional transactivation assays and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders 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.