Submissions for variant NM_000546.6(TP53):c.997C>T (p.Arg333Cys)

dbSNP: rs769934890

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001294069	SCV001737916	likely benign	Li-Fraumeni syndrome 1	2021-04-19	reviewed by expert panel	curation	This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] 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). In this case, a single supporting evidence code (PP3) should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. In summary, TP53 c.997C>T (p.Arg333Cys) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3, BS2_Supporting, BS3.
Ambry Genetics	RCV000164055	SCV000214662	likely benign	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000197833	SCV000254647	uncertain significance	Li-Fraumeni syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the TP53 protein (p.Arg333Cys). This variant is present in population databases (rs769934890, gnomAD 0.004%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, Ewing sarcoma, pancreatic cancer, and/or rectal cancer (PMID: 23894400, 31321604, 33128190). ClinVar contains an entry for this variant (Variation ID: 184745). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 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.
GeneDx	RCV000485066	SCV000568755	uncertain significance	not provided	2019-05-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22187033, 24030381, 30352134, 28861920, 16007150, 26572807, 23894400, 27834926, 27347428, 28993836, 28098136, 14559903, 12826609, 29955864, 30840781, 31016814, 31321604)
Color Diagnostics, LLC DBA Color Health	RCV000164055	SCV000686789	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 333 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 studies have reported for this variant behaves as wildtype in a yeast-based transcriptional transactivation assay and a human cell growth suppression assay (PMID: 12826609, 30224644), but demonstrated intermediate level activity in a colony suppression assay (PMID: 30840781). This variant has been reported in an individual affected with early-onset breast cancer (PMID: 33128190) and an individual affected with Ewing sarcoma and leukemia (IARC database, PMID: 27328919). This variant has been identified in 6/250508 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780790	SCV000918344	uncertain significance	not specified	2018-07-13	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.997C>T (p.Arg333Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 245334 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.997C>T, has been reported in the literature in an individual affected with acute lymphoblastic leukemia (ALL) and Ewing sarcoma, who met the Chompret criteria for Li-Fraumeni Syndrome (Mitchell 2013). This report however does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome (LFS). In a study evaluating an impact on protein function, the variant protein was found to be able to form tetramers and had a partial transcriptional activity (Kawaguchi 2005), however these data do not allow convincing conclusions about the variant effect. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000989701	SCV001140240	benign	Squamous cell carcinoma of the head and neck	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485066	SCV001469931	uncertain significance	not provided	2019-12-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001294069	SCV001482864	uncertain significance	Li-Fraumeni syndrome 1	2019-10-12	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
PreventionGenetics, part of Exact Sciences	RCV003407609	SCV004112940	uncertain significance	TP53-related condition	2023-06-08	criteria provided, single submitter	clinical testing	The TP53 c.997C>T variant is predicted to result in the amino acid substitution p.Arg333Cys. This variant has been reported in patients with adult onset sarcoma, rectal and pancreatic cancer, and breast and/or ovarian cancer, although pathogenicity was not established in these cases (Mitchell et al. 2013. PubMed ID: 23894400; Bittar et al. 2019. PubMed ID: 31321604; Gomes et al. 2020. PubMed ID: 33128190). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7574030-G-A). This variant is interpreted as likely benign by the ClinGen TP53 Variant Curation Expert Panel, in part based on detection of this variant in 3 individuals over the age of 60 without cancer and functional studies not supporting a deleterious effect (https://www.ncbi.nlm.nih.gov/clinvar/variation/184745/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.