Submissions for variant NM_000546.6(TP53):c.488A>G (p.Tyr163Cys)

gnomAD frequency: 0.00001  dbSNP: rs148924904

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000526324	SCV001142560	pathogenic	Li-Fraumeni syndrome	2019-08-28	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 21601526, 8164043). Additionally, there is one proband with a de novo observation of a Li-Fraumeni syndrome core cancer under the age of 5 years with parental confirmation (PS2_Moderate; PMID: 19556618). In summary, the clinical significance of TP53 c.488A>G; p.Tyr163Cys is pathogenic for Li-Fraumeni syndrome: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PS2_Moderate.
GeneDx	RCV000115725	SCV000149634	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of transcriptional activation and growth suppression activities (Kato et al., 2003; Scian et al., 2004; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); 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; This variant is associated with the following publications: (PMID: 12826609, 10519380, 16861262, 14559903, 26585234, 22109999, 16173033, 23929122, 20077503, 8164043, 10671690, 17559811, 17606709, 18685109, 21519010, 24651012, 17764544, 25385265, 25149524, 23967324, 17947339, 15077194, 10753186, 12792784, 15308588, 10871862, 15037740, 10567903, 29167553, 29979965, 30720243, 30630526, 30840781, 33300245, 32817165, 15510160, 21343334, 21601526, 25584008)
Ambry Genetics	RCV000492788	SCV000581096	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-09	criteria provided, single submitter	clinical testing	The p.Y163C variant (also known as c.488A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 488. The tyrosine at codon 163 is replaced by cysteine, an amino acid with highly dissimilar properties. The p.Y163C variant has been observed as a germline alteration a patient with early-onset osteosarcoma and a family history of central nervous system malignancies (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-30). In addition, this alteration was observed in an individual from a LFS family who was diagnosed with adrenocortical carcinoma at the age of 2.5 years and an anaplastic astrocytoma at the age of 14 (Villani et. al. Lancet Oncology. 2011;12:559). This alteration has also been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer (Yi D et al. Hum. Genomics. 2019 01;13:4) This alteration is located in the functionally critical DNA binding domain of the p53 protein. In multiple yeast-based functional studies, this alteration has been shown to be devoid of transactivation capability and demonstrate dominant negative properties (Chappuis PO et al. Int. J. Cancer 1999 Dec;84(6):587-93; Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis 2007 Feb;28(2):289-98; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000526324	SCV000629829	pathogenic	Li-Fraumeni syndrome	2023-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the TP53 protein (p.Tyr163Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 8164043, 11051239, 18685109, 19556618, 25584008, 25757876). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127814). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004019613	SCV004933439	pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15037740, 23246812, 25584008]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19556618, 25584008].
Database of Curated Mutations (DoCM)	RCV000443742	SCV000510057	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423543	SCV000510058	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434251	SCV000510059	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443833	SCV000510060	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427698	SCV000510061	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434917	SCV000510062	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442798	SCV000510063	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424864	SCV000510064	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435593	SCV000510065	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419946	SCV000510066	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430191	SCV000510067	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436926	SCV000510068	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419252	SCV000510069	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429510	SCV000510070	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785334	SCV000923902	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research