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: 43
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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 2024-08-05 reviewed by expert panel curation The NM_000546.6 :c.659A>G variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Cysteine at amino acid 220 (p.Tyr220Cys). This variant has been reported in 9 unrelated probands and/or families meeting Classic and/or Revised Chompret criteria. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 20028212, 9242456, 19101993, 18307025, 20805372, 21761402, 27714481, 10589545, 10432928, 8118819, ClinVar SCV: SCV000183774.8, Internal lab contributors). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 18307025). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 5 families (PP1_Strong; PMIDs: 20028212, 1910993, 10432928, 8118819, 27714481). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, ClinVar GTRs, SCV000183774.8). This variant has an allele frequency of 0.000005932 (7/1179948 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or 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). This variant has 127 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 (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.5625; 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). 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: PS4, PS2_Moderate, PP1_Strong, PM2_Supporting, PS3, PM1, PP3_Moderate, PP4_Moderate (Bayesian Points: 21 points; VCEP specifications version 2.0; 7/24/2024)
GeneDx RCV000213055 SCV000149640 pathogenic not provided 2022-07-27 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, Giacomelli 2018, Kotler 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: 23365691, 17015838, 22923379, 27470445, 27503952, 28091804, 28679691, 27322648, 29853601, 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, 32994724, 32817165, 33087929, 30224644)
Ambry Genetics RCV000115731 SCV000183774 pathogenic Hereditary cancer-predisposing syndrome 2021-11-10 criteria provided, single submitter clinical testing The p.Y220C pathogenic mutation (also known as c.659A>G), located in coding exon 5 of the TP53 gene, 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; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13; Andrade RC et al. Fam Cancer. 2017 04;16:243-248). 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 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). Two other alterations at the same codon, p.Y220H (c.658T>C) and p.Y220N (c.658T>A), are both anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Ambry internal data). Both p.Y220H (c.658T>C) and p.Y220N (c.658T>A) also showed deficient at growth suppression and a dominant negative effect in multiple funtional studies (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, the p.Y220C 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 RCV000232050 SCV000285206 pathogenic Li-Fraumeni syndrome 2024-01-18 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 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%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 22923379, 23630318, 29979965, 30224644). 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 2023-06-05 criteria provided, single submitter clinical testing Variant summary: TP53 c.659A>G (p.Tyr220Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251408 control chromosomes (gnomAD). c.659A>G has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Portwine_2000, Iwaza_2008, Lin_2009, Debelenko_2010, Plon_2011, Wang_2013) and in at least three LFS families where the variant co-segregated with disease in affected members genotyped over two-generations (Birch_1994/Varley_1997, Huusko_1999, Lin_2009). This variant has also been reported in early-onset breast cancer patients (Wilson_2010, Melhem-Bertrandt_2012). These data indicate that the variant is very likely to be associated with disease. Functional studies show that the variant severely compromises the p53 binding and transactivation (e.g. Zachos_1998, Kato_2003, Jordan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 8118819, 20028212, 24702488, 10432928, 18307025, 17015838, 20407015, 19101993, 21761402, 21356188, 10922393, 9242456, 23484829, 20805372, 9662334, 12826609). Fifteen submitters, including an expert panel (ClinGen TP53 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was 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 Diagnostics, LLC DBA Color Health RCV000115731 SCV001339381 pathogenic Hereditary cancer-predisposing syndrome 2022-12-27 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). Functional studies have shown that this variant affects TP53 protein stability (PMID: 17015838, 22869713), 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
Revvity Omics, Revvity RCV000213055 SCV002022390 pathogenic not provided 2019-05-10 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115731 SCV002532699 pathogenic Hereditary cancer-predisposing syndrome 2021-12-23 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002490776 SCV002797313 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5 2022-04-10 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407499 SCV004109437 pathogenic TP53-related disorder 2023-01-30 criteria provided, single submitter clinical testing The TP53 c.659A>G variant is predicted to result in the amino acid substitution p.Tyr220Cys. This variant has been reported in individuals with Li-Fraumeni syndrome, breast cancer, osteosarcoma and adrenal carcinoma (Birch et al. 1994. PubMed ID: 8118819; Varley et al. 1997. PubMed ID: 9242456; Wilson et al. 2010. PubMed ID: 20805372; Melhem-Bertrandt et al. 2011. PubMed ID: 21761402). Functional study showed that this variant impairs transactivation capacities in yeast and mammalian cells (Jordan et al. 2010. PubMed ID: 20407015). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7578190-T-C). This variant is interpreted as likely pathogenic/pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127819/). This variant is interpreted as pathogenic.
Baylor Genetics RCV003460829 SCV004206238 pathogenic Adrenocortical carcinoma, hereditary 2023-09-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000232050 SCV004847987 pathogenic Li-Fraumeni syndrome 2019-12-11 criteria provided, single submitter clinical testing The p.Tyr220Cys variant in TP53 has been previously reported in at least 7 individuals with Li-Fraumeni syndrome associated tumors and segregated with disease in at least 10 affected family members (Birch 1994, Huusko 1999, Monti 2007, Lin 2009, Fostira 2015). It has also been identified in 0.002% (2/113716) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Tyr220Cys variant may impact protein function (Monti 2011); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Tyr220Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3.
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 Papillary renal cell carcinoma type 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 Ovarian neoplasm 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%
Laboratory for Genotyping Development, RIKEN RCV003162539 SCV002758171 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University RCV003997298 SCV004046840 likely pathogenic Adrenal cortex carcinoma no assertion criteria provided clinical testing

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