Submissions for variant NM_000546.6(TP53):c.659A>G (p.Tyr220Cys)

gnomAD frequency: 0.00001  dbSNP: rs121912666

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen	RCV000232050	SCV001142546	pathogenic	Li-Fraumeni syndrome	2019-08-28	reviewed by expert panel	curation	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 are two assays demonstrating loss of function. One study demonstrates a structural defect that destabilizes the protein and another study showed essentially no apoptosis activity in mutant cells (PS3; PMID: 12826609, 20516128, 15037740). This variant has been reported in at least 4 probands meeting classic Li-Fraumeni syndrome criteria (PS4; PMID: 8118819, 10432928, 10589545, 15977174). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 15977174, 9242456, 19101993, 10432928). Additionally, there was a de novo observation in an individual with 10 Classic Li-Fraumeni syndrome spectrum tumors without mention of parental confirmation (PM6; PMID: 18307025). In summary, TP53 c.659A>G; p.Tyr220Cys meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3_Moderate, PM1, PS3, PS4, PP1_Strong, PM6.
GeneDx	RCV000213055	SCV000149640	pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Malcikova 2010, Monti 2011, Kotler 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 23365691, 17015838, 22923379, 27470445, 27503952, 28091804, 28679691, 27322648, 29853601, 30224644, 20407015, 26619011, 24487413, 20128691, 17606709, 24395441, 19367569, 24573247, 21343334, 18307025, 19101993, 8118819, 10432928, 15977174, 20028212, 20805372, 21761402, 23484829, 24702488, 27840695, 27714481, 23315175, 28861920, 29099488, 28369373, 28915717, 28980058, 28076841, 28818333, 29099487, 28643165, 29190505, 28948977, 29979965, 29702446, 30309854, 30032819, 23630318, 30079495, 30720243, 30630526, 31016814, 30840781, 15722483, 10713666, 9627118, 16861262, 15510160, 12826609, 24641375, 31105275, 33300245)
Ambry Genetics	RCV000115731	SCV000183774	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-20	criteria provided, single submitter	clinical testing	The p.Y220C pathogenic mutation (also known as c.659A>G) is located in coding exon 5 of the TP53 gene. This alteration results from an A to G substitution at nucleotide position 659. The tyrosine at codon 220 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in several individuals and families with classic LFS (Birch et al. Cancer Res. 1994 Mar 1;54(5):1298-304; Monti et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13). A yeast based functional study indicated that this alteration leads to transactivation levels less than 25% of wild-type levels. Authors therefore classified this as a severe deficiency allele and felt that this type of alteration may be associated with a higher risk of cancer than partial deficiency alleles (Monti et al. Mol Cancer Res. 2011 Mar;9(3):271-9). Authors of another study determined this mutation creates a new donor splice site (Kouidou et al. Mol Carcinog. 2009 Oct;48(10):895-902). A functional protein microarray showed significantly reduced DNA binding activity compared to wild-type TP53 (Malcikova et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). An IDESA yeast based assay indicated that the p.Y220C alteration leads to significantly reduced protein stability and cell proliferation compare to wild-type (Pittman et al. Genetics. 2012 Nov;192(3):831-42). Furthermore, a functional assay using lymphocytes showed a 75% decrease in TP53 functionality with the p.Y220C alteration compared to wild-type (Zerdoumi Y et al. Hum. Mol. Genet. 2017 07;26(14):2812). In one study, carriers of the p.Y220C pathogenic mutation were found to have a higher incidence of bone cancers compared to other associated Li-Fraumeni tumor types (Xu J et al. Sci Rep. 2014 Feb 27;4:4223). Based on the available evidence, p.Y220C is classified as a pathogenic mutation.
Invitae	RCV000232050	SCV000285206	pathogenic	Li-Fraumeni syndrome	2021-12-01	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 220 of the TP53 protein (p.Tyr220Cys). This variant is present in population databases (rs121912666, gnomAD 0.002%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome, breast cancer and adrenal carcinoma (PMID: 8118819, 10432928, 18307025, 19101993, 20805372, 21761402). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127819). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 22923379, 23630318, 29979965, 30224644). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000232050	SCV000697444	pathogenic	Li-Fraumeni syndrome	2017-04-27	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.659A>G (p.Tyr220Cys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the p53 DNA-binding domain (InterPro). 5/5 in silico tools predict damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000025 (3/119860 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). This variant has been reported as a germline variant in several patients/families with Li-Fraumeni syndrome. This germline variant has also been reported in early-onset breast cancer patients (Wilson_2010; Melhem-Bertrandt_2012). In three LFS families, the variant co-segregated with disease in affected members genotyped over two-generations (Birch_1994/Varley_1997; Huusko_1999; Lin_2009). Functional studies show that the variant severely compromises the p53 binding and transactivation (Jordan_2010; Zachos_1998; TP53 database). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense change at this residue Y220S is also classified as pathogenic in ClinVar by multiple submitters. This variant is located in a mutational hot spot and a small molecule capable of targeting the p.Y220C mutant has been identified (Reviewed by Soussi_2015). Taken together, this variant is classified as pathogenic.
Eurofins NTD LLC (GA)	RCV000213055	SCV000700520	pathogenic	not provided	2017-03-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000232050	SCV000839116	pathogenic	Li-Fraumeni syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213055	SCV000888669	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000213055	SCV001247047	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000115731	SCV001339381	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-18	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 220 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant affects TP53 protein stability (PMID: 17015838, 22869713), and disrupts its transactivation activity (PMID: 21343334, 22822097) and causes loss-of-function in human cell proliferation assay (PMID: 29979965). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome and has been shown to segregate with disease in multiple families (PMID: 8118819, 9242456, 10432928, 11139324, 19101993). This variant has been observed as de novo in an individual with Li-Fraumeni syndrome (PMID: 18307025). In addition, this variant has been reported in individuals affected with breast cancer (PMID: 21118481), ovarian cancer (PMID: 24065105, 25404506), astrocytoma (PMID: 20593220) and glioblastoma (PMID: 25256166). This variant has been identified in 2/251408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo	RCV000433936	SCV001450489	pathogenic	Squamous cell carcinoma of the head and neck		criteria provided, single submitter	case-control
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310212	SCV001499818	pathogenic	Li-Fraumeni syndrome 1	2020-04-02	criteria provided, single submitter	clinical testing
Sema4,Sema4	RCV000115731	SCV002532699	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
Database of Curated Mutations (DoCM)	RCV000417417	SCV000504719	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428097	SCV000504720	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439645	SCV000504721	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418951	SCV000504722	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428791	SCV000504723	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439456	SCV000504724	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423111	SCV000504725	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433936	SCV000504726	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440244	SCV000504727	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423029	SCV000504728	likely pathogenic	Renal cell carcinoma, papillary, 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434614	SCV000504729	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442230	SCV000504730	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423624	SCV000504731	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434300	SCV000504732	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444717	SCV000504733	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425193	SCV000504734	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435063	SCV000504735	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444814	SCV000504736	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425869	SCV000504737	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436553	SCV000504738	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785544	SCV000924116	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
University Health Network,Princess Margaret Cancer Centre	RCV001527468	SCV001738485	pathogenic	B-cell chronic lymphocytic leukemia	2021-03-19	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences	RCV001579295	SCV001805828	pathogenic	Breast carcinoma	2021-08-21	no assertion criteria provided	clinical testing	Invasive Breast Carcinoma grade I EST= + PRO = + HER2 = + KI = 21%
PerkinElmer Genomics	RCV000213055	SCV002022390	pathogenic	not provided	2019-05-10	no assertion criteria provided	clinical testing