ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.935C>G (p.Thr312Ser) (rs145151284)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000204899 SCV001142529 benign Li-Fraumeni syndrome 2019-09-16 reviewed by expert panel curation This variant has an allele frequency of 0.0003605 (0.03%, 9/24,966 alleles) in the African subpopulation of the gnomAD cohort (BS1). This variant also has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, 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). In summary, TP53 c.935C>G; p.Thr312Ser meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BP4, BS3.
Ambry Genetics RCV000129462 SCV000184232 likely benign Hereditary cancer-predisposing syndrome 2017-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Subpopulation frequency in support of benign classification,Other data supporting pathogenic classification,Other data supporting benign classification
GeneDx RCV000213063 SCV000211763 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.935C>G at the cDNA level, p.Thr312Ser (T312S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has been observed in at least one individual with a personal and/or family history suggestive of Li-Fraumeni syndrome (Bougeard 2008). Additionally, TP53 Thr312Ser has been identified in an individual with a head and neck cancer and in an individual with pancreatic cancer (Mafune 2015, Yang 2016). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Thr312Ser was observed at an allele frequency of 0.029% (7/24028) in individuals of African ancestry in large population cohorts (Lek 2016). TP53 Thr312Ser is not located within a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Thr312Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204899 SCV000261663 uncertain significance Li-Fraumeni syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 312 of the TP53 protein (p.Thr312Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs145151284, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family with suspected Li-Fraumeni syndrome (PMID: 18511570), an individual with pancreatic cancer (PMID: 27449771), and an individual with acute lymphoblastic leukemia (PMID: 27619989). ClinVar contains an entry for this variant (Variation ID: 141102). An experimental study in yeast has shown that this missense change does not impact TP53 transcriptional activity (PMID: 12826609). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
Counsyl RCV000411116 SCV000488345 uncertain significance Li-Fraumeni syndrome 1 2016-03-03 criteria provided, single submitter clinical testing
Mendelics RCV000204899 SCV000839106 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129462 SCV000910895 benign Hereditary cancer-predisposing syndrome 2015-11-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213063 SCV001134881 uncertain significance not provided 2019-06-13 criteria provided, single submitter clinical testing
Mendelics RCV000989705 SCV001140244 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing

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