Submissions for variant NM_000546.6(TP53):c.346T>G (p.Ser116Ala)

gnomAD frequency: 0.00001  dbSNP: rs989692988

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804275	SCV000944177	uncertain significance	Li-Fraumeni syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 116 of the TP53 protein (p.Ser116Ala). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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, 16687402, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 649358). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (ALL) (PMID: 29300620).
Ambry Genetics	RCV001020381	SCV001181854	likely benign	Hereditary cancer-predisposing syndrome	2023-07-05	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.
Genome-Nilou Lab	RCV001020381	SCV002582106	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290445	SCV002582669	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478506	SCV004221353	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been only briefly reported in a pediatric brain tumor along with other variants (PMID: 31133068 (2019)). Functional studies have described the variant to retain antiproliferative activity and as being functional (PMIDs: 29979965 (2018), 30224644 (2018) see also PHANTM (https://mutantp53.broadinstitute.org/), 12826609 (2003) see also The TP53 Database (https://tp53.isb-cgc.org/)), however, further research is needed. The frequency of this variant in the general population, 0.000008 (2/251192 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV004569609	SCV005054327	uncertain significance	Adrenocortical carcinoma, hereditary	2024-03-05	criteria provided, single submitter	clinical testing