ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.877G>T (p.Gly293Trp) (rs587780076)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000462367 SCV001429620 likely benign Li-Fraumeni syndrome 2020-08-11 reviewed by expert panel curation Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.877G>T (p.Gly293Trp) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: BS3; BS2_Supporting.
GeneDx RCV000213062 SCV000149650 uncertain significance not provided 2020-06-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: retained transactivation activity (Kato 2003, Monti 2011); Observed in individuals with sarcoma, glioblastoma, neurofibromatosis, and/or breast cancer (Chung 1991, Mitchell 2013, Tung 2016); This variant is associated with the following publications: (PMID: 17606709, 26976419, 22045683, 15924253, 30352134, 1686725, 24729566, 25801821, 23894400, 26367797, 26659599, 12826609, 8829653, 26933808, 21343334, 30840781)
Ambry Genetics RCV000115741 SCV000187101 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing The p.G293W variant (also known as c.877G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 877. The glycine at codon 293 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been described as a germline alteration in at least one individual with two tumors and no family history of cancer (Monti P, et al. (2007) Clin. Cancer Res. 13(13):3789-95). This alteration was detected in a male patient meeting Chompret criteria (Mitchell G, PLoS ONE 2013 ; 8(7):e69026), and in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). Yeast-based functional studies showed this alteration to have transactivation activity similar to wild type (Kato S et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Jul;100:8424-9; Monti P, et al. (2011) Mol. Cancer Res. 9(3):271-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000410614 SCV000488448 uncertain significance Li-Fraumeni syndrome 1 2016-04-07 criteria provided, single submitter clinical testing
Invitae RCV000462367 SCV000545297 uncertain significance Li-Fraumeni syndrome 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 293 of the TP53 protein (p.Gly293Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with glioblastoma and neurofibromatosis, sarcoma, and breast cancer (PMID: 1686725, 23894400, 26976419). ClinVar contains an entry for this variant (Variation ID: 127826). This variant has been reported to have conflicting or insufficient data to determine the effect on TP53 protein function (PMID: 17606709, 21343334, 12826609, 30840781, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000115741 SCV000691660 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-27 criteria provided, single submitter clinical testing This missense variant replaces glycine with tryptophan at codon 293 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be functional in yeast transcription activation assays (IARC database and PMID: 12826609, 17606709, 21343334) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in a 17 year-old affected with glioblastoma and diagnosed with neurofibromatosis type 1 (PMID: 1686725) and in individuals affected with adult-onset sarcoma (PMID: 23894400) and breast cancer (PMID: 26976419). This variant has been identified in 3/282876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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