Submissions for variant NM_000546.6(TP53):c.578A>C (p.His193Pro)

gnomAD frequency: 0.00001  dbSNP: rs786201838

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991151	SCV001142566	pathogenic	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.578A>C variant in TP53 is a missense variant predicted to cause substitution of histidine by proline at amino acid 193 (p.His193Pro). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.5922; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). At least one individual with this variant was found to have a variant allele fraction of 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: SCV002651939.1). This variant has an allele frequency of 6.196e-7 (1/1614048 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has 8 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3_Moderate, PS2, PP4, PM2_Supporting, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024)
Color Diagnostics, LLC DBA Color Health	RCV001525967	SCV001736190	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 193 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 have shown that this variant disrupts TP53 transactivation activity, exhibits loss-of-function and dominant negative activity in human cell growth suppression assays, and results in loss-of-function in a human cell proliferation assay (PMID: (PMID: 22822097, 29979965, 30224644). This variant has been reported in 3 individuals meeting Chompret criteria affected with choroid plexus carcinoma and adrenocortical carcinoma (PMID: 20308654, 27501770), one of which was observed to occur de novo (PMID: 25584008), and another individual with soft tissue sarcoma and lung cancer (PMID: 28369373). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001525967	SCV002651939	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-14	criteria provided, single submitter	clinical testing	The p.H193P pathogenic mutation (also known as c.578A>C), located in coding exon 5 of the TP53 gene, results from an A to C substitution at nucleotide position 578. The histidine at codon 193 is replaced by proline, an amino acid with similar properties. This mutation has been reported as germline in a one year old child diagnosed with both adrenocortical carcinoma and choroid plexus tumor (Tabori U et al. Cancer Res. 2007 Feb;67:1415-8). This has also been reported in as germline in a child diagnosed with two LFS related tumors by the age of 5 where parental testing confirmed this was a de novo finding (Gonzalez KD et al. J Med Genet> 2009 Oct;46:689-93). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991151	SCV004296705	pathogenic	Li-Fraumeni syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 193 of the TP53 protein (p.His193Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 17308077, 33674644). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376612). 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 with a positive predictive value of 97.5%. This variant disrupts the p.His193 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887414, 21343334, 22265402, 25945745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Database of Curated Mutations (DoCM)	RCV000417520	SCV000508526	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428197	SCV000508527	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435420	SCV000508528	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418213	SCV000508529	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428877	SCV000508530	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439568	SCV000508531	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422374	SCV000508532	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429577	SCV000508533	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440128	SCV000508534	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422912	SCV000508535	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433585	SCV000508536	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442541	SCV000508537	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423516	SCV000508538	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434205	SCV000508539	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445292	SCV000508540	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427668	SCV000508541	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434933	SCV000508542	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444985	SCV000508543	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424851	SCV000508544	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435566	SCV000508545	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only