Submissions for variant NM_000546.6(TP53):c.575A>G (p.Gln192Arg)

dbSNP: rs730882002

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161029	SCV000211750	uncertain significance	not provided	2014-05-07	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.575A>G at the cDNA level, p.Gln192Arg (Q192R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has been observed as a somatic mutation in several cancers but has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism (IARC TP53 Database). TP53 Gln192Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Gln192Arg occurs at a position that is well conserved across species and is located in the regions responsible for interaction with HIPK1, ZNF385A, FBXO42, and AXIN1 (UniProt). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Gln192Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001024490	SCV001186513	likely benign	Hereditary cancer-predisposing syndrome	2024-06-24	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	RCV001371035	SCV001567585	uncertain significance	Li-Fraumeni syndrome	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 192 of the TP53 protein (p.Gln192Arg). 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: 182931). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Genome-Nilou Lab	RCV001024490	SCV002582055	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288689	SCV002582413	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462108	SCV004206279	uncertain significance	Adrenocortical carcinoma, hereditary	2023-05-18	criteria provided, single submitter	clinical testing