Total submissions: 24
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000991151 | SCV001142566 | pathogenic | Li-Fraumeni syndrome | 2019-08-28 | reviewed by expert panel | curation | This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). 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 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 28369373, 20308654). Additionally, there is one proband with a de novo observation of a Li-Fraumeni syndrome core cancer under the age of 5 years without parental confirmation (PM6; PMID: 25584008). In summary, the clinical significance of TP53 c.578A>C; p.His193Pro is pathogenic for Li-Fraumeni syndrome: PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting, PM6. |
Color Diagnostics, |
RCV001525967 | SCV001736190 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-06-22 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with proline at codon 193 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). Experimental functional studies have shown that this variant disrupts TP53 transactivation activity, exhibits loss-of-function and dominant negative activity in human cell growth suppression assays, and results in loss-of-function in a human cell proliferation assay (PMID: (PMID: 22822097, 29979965, 30224644). This variant has been reported in 3 individuals meeting Chompret criteria affected with choroid plexus carcinoma and adrenocortical carcinoma (PMID: 20308654, 27501770), one of which was observed to occur de novo (PMID: 25584008), and another individual with soft tissue sarcoma and lung cancer (PMID: 28369373). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
Ambry Genetics | RCV001525967 | SCV002651939 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-14 | criteria provided, single submitter | clinical testing | The p.H193P pathogenic mutation (also known as c.578A>C), located in coding exon 5 of the TP53 gene, results from an A to C substitution at nucleotide position 578. The histidine at codon 193 is replaced by proline, an amino acid with similar properties. This mutation has been reported as germline in a one year old child diagnosed with both adrenocortical carcinoma and choroid plexus tumor (Tabori U et al. Cancer Res. 2007 Feb;67:1415-8). This has also been reported in as germline in a child diagnosed with two LFS related tumors by the age of 5 where parental testing confirmed this was a de novo finding (Gonzalez KD et al. J Med Genet> 2009 Oct;46:689-93). 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 variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV000991151 | SCV004296705 | pathogenic | Li-Fraumeni syndrome | 2023-11-14 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 193 of the TP53 protein (p.His193Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 17308077, 33674644). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376612). 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%. This variant disrupts the p.His193 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887414, 21343334, 22265402, 25945745). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Database of Curated Mutations |
RCV000417520 | SCV000508526 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428197 | SCV000508527 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435420 | SCV000508528 | likely pathogenic | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418213 | SCV000508529 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428877 | SCV000508530 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439568 | SCV000508531 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422374 | SCV000508532 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429577 | SCV000508533 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440128 | SCV000508534 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422912 | SCV000508535 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433585 | SCV000508536 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442541 | SCV000508537 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423516 | SCV000508538 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434205 | SCV000508539 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445292 | SCV000508540 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427668 | SCV000508541 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434933 | SCV000508542 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444985 | SCV000508543 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424851 | SCV000508544 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435566 | SCV000508545 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only |