Total submissions: 52
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000197114 | SCV001142549 | pathogenic | Li-Fraumeni syndrome | 2019-08-28 | reviewed by expert panel | curation | This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 3 probands meeting classic Li-Fraumeni syndrome and 2 probands meeting Chompret criteria (PS4; PMID: 1565143, 9242456, 15381368, 7887414). There is a de novo observation of a proband with adrenocortical carcinoma with parental confirmation (PS2; PMID: 15381368). In summary, TP53 c.743G>A; p.Arg248Gln meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4, PS2. |
Gene |
RCV000235221 | SCV000149645 | pathogenic | not provided | 2018-10-05 | criteria provided, single submitter | clinical testing | This pathogenic variant is denoted TP53 c.743G>A at the cDNA level, p.Arg248Gln (R248Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been observed in several Li-Fraumeni or Li-Fraumeni-like families and has also been reported as an apparently de novo heterozygous or mosaic finding in individuals meeting Chompret criteria (Toguchida 1992, Monti 2007, Prochazkova 2009, Masciari 2011, Villani 2011, Behjati 2014, Patrier-Sallebert 2015, Parsons 2016, Sherborne 2016). Functional studies have found that TP53 Arg248Gln impacts DNA binding, apoptosis, growth suppression, and transactivation activities and leads to a dominant-negative effect (Lomax 1998, Dearth 2007, Malcikova 2010, Monti 2011). This variant is also reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional studies by Kato et al. (2003). TP53 Arg248Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the current evidence, we consider this variant to be pathogenic. |
Ambry Genetics | RCV000115736 | SCV000185472 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-09-07 | criteria provided, single submitter | clinical testing | ​<span style="background-color:initial">The p.R248Q (also known as c.743G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. <span style="background-color:initial">This alteration results from a G to A substitution at nucleotide position 743. The arginine at codon 248 is replaced by glutamine, an amino acid with some similar properties. <span style="background-color:initial">This alteration was first described as a de novo<span style="background-color:initial"> mutation in a woman with multiple primary osteosarcomas and bilateral breast cancer and her daughter with childhood-onset sarcoma (Toguchida J et al. N Engl J Med<span style="background-color:initial">. 1992 May 14;326(20):1301-8). In addition, p.R248Q has been classified as a severe deficiency allele based on an associated transactivation activity of less than 25% compared to wildtype p53 function (Monti P et al. Clin Cancer Res.<span style="background-color:initial"> 2007 Jul 1;13(13):3789-95). This alteration is located in the DNA binding domain, and has been shown to be involved in DNA binding through crystal structure analysis (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64).<span style="background-color:initial"> To date, this alteration has been detected in numerous LFS families and other pathogenic missense mutations at codon 248 have been reported (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat.<span style="background-color:initial"> 2007 Jun;28(6):622-9; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. <span style="background-color:initial">2003;21:577-581). Based on the available evidence, this alteration is classified as a pathogenic mutation. |
EGL Genetic Diagnostics, |
RCV000235221 | SCV000232078 | pathogenic | not provided | 2014-06-09 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000197114 | SCV000253851 | pathogenic | Li-Fraumeni syndrome | 2020-01-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 248 of the TP53 protein (p.Arg248Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs11540652, ExAC 0.02%). This variant was reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526, 7887414, 21305319). ClinVar contains an entry for this variant (Variation ID: 12356). Experimental studies have shown that this missense change severely affects the functional activity of the p53 protein, abolishing its DNA-binding and transcriptional transactivation activities. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). For these reasons, this variant has been classified as Pathogenic. |
University of Washington Department of Laboratory Medicine, |
RCV000115736 | SCV000266133 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
Color | RCV000115736 | SCV000686766 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-04-14 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000013150 | SCV000785422 | likely pathogenic | Li-Fraumeni syndrome 1 | 2017-07-27 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000115736 | SCV000821785 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-01 | criteria provided, single submitter | clinical testing | This sequence change replaces Arginine with Glutamine at codon 248 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein. There is a small physiochemical difference between arginine and glutamine (Grantham Score 43).This variant is present in population databases at a very low frequency (rs11540652, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526).Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. Moreover, experimental studies have shown that this missense change severely affects the functional activity of the p53 protein. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). The mutation database Clinvar contains entries for this variant (Variation ID:12356). |
Mendelics | RCV000197114 | SCV000839112 | pathogenic | Li-Fraumeni syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000763417 | SCV000894154 | pathogenic | Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000235221 | SCV001134877 | pathogenic | not provided | 2018-11-21 | criteria provided, single submitter | clinical testing | The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity confirmed. |
Integrated Genetics/Laboratory Corporation of America | RCV000197114 | SCV001363225 | pathogenic | Li-Fraumeni syndrome | 2019-09-20 | criteria provided, single submitter | clinical testing | Variant summary: TP53 c.743G>A (p.Arg248Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes (gnomAD). c.743G>A has been reported in the literature in multiple individuals/families affected with Li-Fraumeni or Li-Fraumeni-like syndromes (e.g. Haque_2018, Rapakko_2001, Vahteristo_2001, Villani_2011) while, it was also reported in a LFS patient with a suggested de novo occurrence (Bendig_2004). These data indicate that the variant is very likely to be associated with disease. Functional studies demonstrate that the R248Q substitution impairs the DNA binding capability of TP53 essential for its tumor suppressor function (Merabet_2010), and the variant exhibited less than 25% of wild-type transcriptional transactivation activity. Additional studies have classified this variant as a severe deficiency allele with a dominant negative effect (Monti_2011, Zerdoumi_2017). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Clinical Genetics Karolinska University Hospital, |
RCV000235221 | SCV001449921 | likely pathogenic | not provided | 2018-06-25 | criteria provided, single submitter | clinical testing | |
Institute of Biochemistry, |
RCV001270275 | SCV001450492 | pathogenic | Familial cancer of breast | criteria provided, single submitter | case-control | ||
OMIM | RCV000013150 | SCV000033397 | pathogenic | Li-Fraumeni syndrome 1 | 2000-05-15 | no assertion criteria provided | literature only | |
Pathway Genomics | RCV000013150 | SCV000190000 | pathogenic | Li-Fraumeni syndrome 1 | 2014-07-24 | no assertion criteria provided | clinical testing | |
CSER _CC_NCGL, |
RCV000148913 | SCV000190659 | pathogenic | Sarcoma | 2014-06-01 | no assertion criteria provided | research | |
Database of Curated Mutations |
RCV000445244 | SCV000504693 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426606 | SCV000504694 | likely pathogenic | Neoplasm | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437291 | SCV000504695 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419135 | SCV000504696 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426359 | SCV000504697 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437935 | SCV000504698 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420727 | SCV000504699 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430513 | SCV000504700 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441226 | SCV000504701 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417916 | SCV000504702 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428591 | SCV000504703 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438410 | SCV000504704 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421194 | SCV000504705 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432778 | SCV000504706 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439963 | SCV000504707 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421893 | SCV000504708 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432587 | SCV000504709 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445235 | SCV000504710 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426233 | SCV000504711 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433424 | SCV000504712 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444656 | SCV000504713 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427709 | SCV000504714 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437518 | SCV000504715 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420303 | SCV000504716 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424869 | SCV000504717 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435533 | SCV000504718 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Donald Williams Parsons Laboratory, |
RCV000013150 | SCV000599966 | pathogenic | Li-Fraumeni syndrome 1 | 2012-12-27 | no assertion criteria provided | research | This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma). |
Mayo Clinic Genetic Testing Laboratories, |
RCV000235221 | SCV000692073 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Sciences Centre, |
RCV000589336 | SCV000693734 | pathogenic | Malignant Colorectal Neoplasm | 2016-04-12 | no assertion criteria provided | research | |
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785344 | SCV000923912 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research | |
Xiao lab, |
RCV000790860 | SCV000930032 | likely pathogenic | Lymphoma | 2019-07-25 | no assertion criteria provided | clinical testing | |
Xiao lab, |
RCV000424869 | SCV001132099 | likely pathogenic | Multiple myeloma | 2019-08-31 | no assertion criteria provided | clinical testing | |
Institute of Medical Sciences, |
RCV001255671 | SCV001432236 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research | |
Human Genome Sequencing Center Clinical Lab, |
RCV001257519 | SCV001434345 | pathogenic | Rhabdomyosarcoma (disease) | 2020-09-01 | no assertion criteria provided | provider interpretation |