Submissions for variant NM_000546.6(TP53):c.530C>T (p.Pro177Leu)

gnomAD frequency: 0.00001  dbSNP: rs751477326

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477631	SCV000545313	likely pathogenic	Li-Fraumeni syndrome	2023-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 177 of the TP53 protein (p.Pro177Leu). ClinVar contains an entry for this variant (Variation ID: 406583). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). This variant is present in population databases (no rsID available, gnomAD 0.0009%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9627118, 12826609, 16861262, 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 expected to disrupt TP53 function.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759377	SCV000888668	uncertain significance	not provided	2018-02-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348300	SCV002647225	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The p.P177L variant (also known as c.530C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 530. The proline at codon 177 is replaced by leucine, an amino acid with similar properties. This alteration was observed in 1/7051 unselected female breast cancer patients and not in any of the 11241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients or any of the 12490 male controls of Japanese ancestry. The authors reported this variant as a VUS (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000477631	SCV004842507	uncertain significance	Li-Fraumeni syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 177 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies in yeast and human cells reported inconsistent or inconclusive results in transcriptional activation assays and human cell growth suppression and proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has not been reported in individuals affected with Li-Fraumeni syndrome in the literature. The variant has been reported in individuals affected with breast cancer (PMID: 30287823, 33471991). Another variant at this codon (p.Pro177Arg) is reported as disease causing in ClinVar (Variation ID:458547). This variant has been identified in 1/251300 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	RCV000759377	SCV005327533	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with breast cancer (PMID: 30287823); This variant is associated with the following publications: (PMID: 15510160, 29979965, 12826609, 22768918, 30224644, 27501770, 20421238, 26787237, 30562681, 26981779, 27879972, 31064327, 30650148, 15541116, 26933808, 30661751, 10753186, 29973234, 26164085, 21118481, 37024846, 30840781, 9627118, 16861262, 9010218, 23117049, 30287823)