Submissions for variant NM_000546.6(TP53):c.873G>C (p.Lys291Asn)

dbSNP: rs372613518

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774787	SCV000908786	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 291 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental studies have shown that this variant functions as wild-type TP53 in yeast-based transcriptional transactivation assays, and human cell growth and proliferation assays (PMID: 30224644, 29979965, 12826609). 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	RCV000820689	SCV000961412	uncertain significance	Li-Fraumeni syndrome	2023-07-08	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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 629930). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 291 of the TP53 protein (p.Lys291Asn).
Genome-Nilou Lab	RCV000774787	SCV002581986	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290023	SCV002583088	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000774787	SCV002682021	likely benign	Hereditary cancer-predisposing syndrome	2021-01-15	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.