ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.375G>A (p.Thr125=) (rs55863639)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218743 SCV000277767 pathogenic Hereditary cancer-predisposing syndrome 2018-02-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Last nucleotide of exon,Well-characterized mutation at same position
GeneDx RCV000483667 SCV000567386 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.375G>A at the DNA level. Although this variant is silent at the coding level, preserving a Threonine at codon 125, it has been demonstrated via RT-PCR to cause aberrant splicing (Warneford 1992, Varley 1997, Varley 2001). This variant has been reported in several individuals meeting either classic Li-Fraumeni syndrome or Chompret criteria (Warneford 1992, Varley 2001, Bougeard 2008, Ruijs 2010, Silva 2012, Hettmer 2014, Wasserman 2015). TP53 c.375G>A was not observed in large population cohorts (Lek 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000154460 SCV000697430 pathogenic Li-Fraumeni syndrome 2016-10-21 criteria provided, single submitter clinical testing Variant summary: The TP53 c.375G>A (p.Thr125Thr) variant causes a synonymous change, however, the variant is located at last 3' position of exon 4 that could affect splicing. 4/5 splice prediction tools predict a significant impact on normal splicing, which is further supported by multiple functional studies. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals including cosegregation with the disease within families. In addition, multiple reputable diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000154460 SCV000629813 pathogenic Li-Fraumeni syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change affects codon 125 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. This variant also falls at the last nucleotide of exon 4 of the TP53 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Li-Fraumeni syndrome (PMID: 1467311, 11420676, 18511570, 21348412, 22170717, 9242456, 24382691, 25945745, 27501770) and adrenocortical carcinoma (PMID: 22170717, 25584008) and was reported to segregate with TP53-related cancers in two of these families (PMID: 1467311, 9242456). ClinVar contains an entry for this variant (Variation ID: 177825). Experimental studies have shown that this variant results in altered TP53 mRNA splicing that will likely result in an absent or non-functional protein product (PMID: 1467311, 11420676). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154460 SCV000204129 pathogenic Li-Fraumeni syndrome 2008-07-31 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000483667 SCV000692091 pathogenic not provided no assertion criteria provided clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000483667 SCV000925737 not provided not provided no assertion provided in vitro
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483667 SCV000602269 pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing

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