Submissions for variant NM_000546.6(TP53):c.554G>A (p.Ser185Asn)

gnomAD frequency: 0.00004  dbSNP: rs150607408

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000233843	SCV001432166	likely benign	Li-Fraumeni syndrome	2025-01-16	reviewed by expert panel	curation	The NM_000546.6: c.554G>A variant in TP53 is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 185 (p.Ser185Asn). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.159418; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BP4_Moderate, BS3. (Bayesian Points: -6; VCEP specifications version 2.1; 1/16/2025).
Ambry Genetics	RCV000129849	SCV000184666	likely benign	Hereditary cancer-predisposing syndrome	2021-02-23	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	RCV000233843	SCV000285201	uncertain significance	Li-Fraumeni syndrome	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 185 of the TP53 protein (p.Ser185Asn). This variant is present in population databases (rs150607408, gnomAD 0.007%). This missense change has been observed in individual(s) with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 141359). Invitae Evidence Modeling incorporating data from in vitro 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.
Counsyl	RCV000662659	SCV000785348	uncertain significance	Li-Fraumeni syndrome 1	2017-07-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129849	SCV000906430	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 185 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not affect transactivation activity of TP53 protein in yeast assays (PMID: 12826609), showed no dominant-negative or loss of function in human cell growth suppression assays (PMID: 30224644), and was functional in a human cell proliferation assay (PMID: 29979965). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519). This variant has been identified in 1/251340 chromosomes 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.
GeneDx	RCV001552973	SCV001773759	likely benign	not provided	2019-08-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29979965, 20436685)
Myriad Genetics, Inc.	RCV000662659	SCV004017848	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321512	SCV004026690	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001552973	SCV004221361	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251340 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with osteosarcoma (PMID: 25896519 (2015)). In a large breast cancer association study, the variant was found both in individuals with breast cancer as well as healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/TP53). Functional studies report the variant does not impact TP53 protein function (PMIDs: 30224644 (2018), 29979965 (2018), 12826609 (2003)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000233843	SCV004823787	uncertain significance	Li-Fraumeni syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 185 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not affect transactivation activity of TP53 protein in yeast assays (PMID: 12826609), showed no dominant-negative or loss of function in human cell growth suppression assays (PMID: 30224644), and was functional in a human cell proliferation assay (PMID: 29979965). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519). This variant has been identified in 1/251340 chromosomes 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.