Total submissions: 37
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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. |
Gene |
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, |
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 |
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 | |
Ce |
RCV000213055 | SCV001247047 | pathogenic | not provided | 2019-02-01 | criteria provided, single submitter | clinical testing | |
Color Health, |
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, |
RCV000433936 | SCV001450489 | pathogenic | Squamous cell carcinoma of the head and neck | criteria provided, single submitter | case-control | ||
Department of Molecular Diagnostics, |
RCV001310212 | SCV001499818 | pathogenic | Li-Fraumeni syndrome 1 | 2020-04-02 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000115731 | SCV002532699 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-23 | criteria provided, single submitter | curation | |
Database of Curated Mutations |
RCV000417417 | SCV000504719 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428097 | SCV000504720 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439645 | SCV000504721 | likely pathogenic | Acute myeloid leukemia | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418951 | SCV000504722 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428791 | SCV000504723 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439456 | SCV000504724 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423111 | SCV000504725 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000440244 | SCV000504727 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423029 | SCV000504728 | likely pathogenic | Renal cell carcinoma, papillary, 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434614 | SCV000504729 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442230 | SCV000504730 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423624 | SCV000504731 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434300 | SCV000504732 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444717 | SCV000504733 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425193 | SCV000504734 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435063 | SCV000504735 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444814 | SCV000504736 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425869 | SCV000504737 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436553 | SCV000504738 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785544 | SCV000924116 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research | |
University Health Network, |
RCV001527468 | SCV001738485 | pathogenic | B-cell chronic lymphocytic leukemia | 2021-03-19 | no assertion criteria provided | clinical testing | |
Medical Genetics Laboratory, |
RCV001579295 | SCV001805828 | pathogenic | Breast carcinoma | 2021-08-21 | no assertion criteria provided | clinical testing | Invasive Breast Carcinoma grade I EST= + PRO = + HER2 = + KI = 21% |
Perkin |
RCV000213055 | SCV002022390 | pathogenic | not provided | 2019-05-10 | no assertion criteria provided | clinical testing |