ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs121912666
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Total submissions: 37
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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

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