Total submissions: 33
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000568814 | SCV000665156 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-12 | criteria provided, single submitter | clinical testing | The p.R273L pathogenic mutation (also known as c.818G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 818. The arginine at codon 273 is replaced by leucine, an amino acid with dissimilar properties. This mutation occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain. Several other mutations have been described at this position and are associated with a classic LFS-associated tumor spectrum (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). This specific alteration has been reported in a family meeting Chompret criteria for Li-Fraumeni Syndrome, and has been identified as a de novo mutation in a patient diagnosed with adrenaocortical carcinoma and rhabdomyosarcoma at 1 year of age (Bougeard Get al. J. Clin. Oncol. 2015 Jul; 33(21):2345-52; Chompret A et al. Br. J. Cancer 2000 Jun; 82(12):1932-7). Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti, P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth Let al. Carcinogenesis 2007 Feb; 28(2):289-98). 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). Based on crystal structure analysis, this position has been shown to be involved in DNA contact and binding (Martin A et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R273L is classified as a pathogenic mutation. |
Invitae | RCV000822080 | SCV000962866 | pathogenic | Li-Fraumeni syndrome | 2023-09-10 | criteria provided, single submitter | clinical testing | This variant disrupts the p.273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 273 of the TP53 protein (p.Arg273Leu). This variant is present in population databases (rs28934576, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni-associated cancers (PMID: 10864200, 26014290). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376655). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 12826609, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV001539823 | SCV001757640 | pathogenic | not provided | 2022-12-23 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of apoptotic activity, and exhibits a dominant-negative effect (Monti et al., 2007; Monti et al., 2011; Giacomelli et al., 2018; Kotler et al., 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: 10519380, 16322298, 9738975, 12792784, 16000567, 8336941, 10753186, 9546439, 8062826, 11429705, 30840781, 15510160, 29922827, 9407971, 17606709, 21343334, 30720243, 29752319, 10864200, 29092957, 17311302, 32658383, 16861262, 21484931, 21552135, 8649776, 17540308, 15161705, 27813088, 15037740, 11793474, 9242456, 30224644, 26619011, 20693561, 12826609, 1565144, 29979965, 26014290) |
Genome- |
RCV000568814 | SCV002582451 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002289534 | SCV002583113 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002502455 | SCV002784210 | 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 | 2022-05-24 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000822080 | SCV004848115 | pathogenic | Li-Fraumeni syndrome | 2017-09-11 | criteria provided, single submitter | clinical testing | The p.Arg273Leu variant in TP53 has been reported in 6 individuals with TP53-associated cancers, including 1 that was de novo (paternity- confirmed; Chompret 2000, Kyritsis 1994, Monti 2007, Dong 2011 and Bougeard 2015). This variant has also been reported in ClinVar (Variation ID 376655) and has been identified in 1/111470 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28934576), though the allele ratio suggests it may be somatic. Arginine at position 273 is a mutational hotspot in many different types of cancers, and different changes at the same codon (p.Arg273Cys and p.Arg273His) have been reported in multiple families with Li-Fraumeni syndrome. Computational prediction tools suggest that the p.Arg273Leu variant may impact the protein. In vitro functional studies provide some evidence that the p.Arg273Leu variant may impact protein function (Kawamura 1996, Monti 2011, Ory 1994). In summary, the p.Arg273Leu variant is pathogenic Li-Fraumeni syndrome in an autosomal dominant inheritance. |
Database of Curated Mutations |
RCV000423981 | SCV000509434 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434695 | SCV000509435 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444989 | SCV000509436 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427314 | SCV000509437 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437048 | SCV000509438 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444109 | SCV000509439 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426132 | SCV000509440 | likely pathogenic | Adrenal cortex carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436818 | SCV000509441 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418738 | SCV000509442 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429444 | SCV000509443 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435767 | SCV000509444 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418536 | SCV000509445 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428692 | SCV000509446 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438507 | SCV000509447 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421259 | SCV000509448 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431067 | SCV000509449 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441792 | SCV000509450 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423633 | SCV000509451 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434296 | SCV000509452 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442241 | SCV000509453 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423490 | SCV000509454 | likely pathogenic | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433315 | SCV000509455 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444782 | SCV000509456 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425890 | SCV000509457 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Genome Sciences Centre, |
RCV000515526 | SCV000611151 | likely pathogenic | Metastatic pancreatic neuroendocrine tumours | 2017-11-01 | no assertion criteria provided | research | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785524 | SCV000924096 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |