Submissions for variant NM_000546.6(TP53):c.659A>C (p.Tyr220Ser)

dbSNP: rs121912666

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472593	SCV000545350	pathogenic	Li-Fraumeni syndrome	2022-03-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr220 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18307025, 19101993, 20028212, 20407015, 24603336). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 15977174, 21343334). 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 expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 12383). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-associated cancers (PMID: 15977174, 17606709, 19556618, 20234365). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 220 of the TP53 protein (p.Tyr220Ser).
Ambry Genetics	RCV003162249	SCV003856751	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	The p.Y220S pathogenic mutation (also known as c.659A>C), located in coding exon 5 of the TP53 gene, results from an A to C substitution at nucleotide position 659. The tyrosine at codon 220 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in individuals with personal histories of Li Fraumeni syndrome core cancers including breast cancer, osteosarcoma and central nervous system tumors (Joachim T et al. Int J Cancer, 2001 Oct;94:218-21; Gonzalez KD et al. J Med Genet, 2009 Oct;46:689-93; Melhem-Bertrandt A et al. Cancer, 2012 Feb;118:908-13). 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 has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Another alteration at the same codon, p.Y220H (c.658T>C), has also been detected in individuals at an allele fraction that is suggestive of clonal hematopoiesis and is anticipated to result in a decrease in structural stability (Ambry internal data; Cho Y, Science 1994 Jul; 265(5170):346-55). This amino acid position is highly conserved in available vertebrate species. The p.Y220S variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
OMIM	RCV000013183	SCV000033430	pathogenic	Li-Fraumeni syndrome 1	2005-08-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443214	SCV000510209	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425801	SCV000510210	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436486	SCV000510211	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418406	SCV000510212	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429097	SCV000510213	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435597	SCV000510214	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417473	SCV000510215	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428157	SCV000510216	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441465	SCV000510217	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424238	SCV000510218	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430581	SCV000510219	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441285	SCV000510220	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423167	SCV000510221	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433786	SCV000510222	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445060	SCV000510223	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422874	SCV000510224	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432708	SCV000510225	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444276	SCV000510226	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425300	SCV000510227	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785481	SCV000924053	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research