ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.736A>G (p.Met246Val) (rs483352695)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000161036 SCV000276627 pathogenic Hereditary cancer-predisposing syndrome 2016-10-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785556 SCV000924128 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000460370 SCV000545351 likely pathogenic Li-Fraumeni syndrome 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 246 of the TP53 protein (p.Met246Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate in a single family in which 9 carriers of the variant were affected with either breast or prostate cancer (PMID: 26534844). Three of these individuals had a second cancer type (lung cancer or melanoma) in addition to their breast or prostate cancer. This variant has also been reported in an individual affected with Wilm's tumor, whose mother also carried the variant and was affected with both cervical cancer and glioma (PMID: 8075648). ClinVar contains an entry for this variant (Variation ID: 100815). Experimental studies of transcriptional activity in yeast assays using multiple different promoters indicate that this missense change is non-functional and acts in a dominant-negative manner (PMID: 21343334, 17606709, 12826609). In addition, a study performed in rat embryo fibroblasts found that this variant exhibits reduced tumor suppressing ability when co-transfected with Ras (PMID: 1918170). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Richard Lifton Laboratory, Yale University School of Medicine RCV000087173 SCV000120035 probable-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Richard Lifton Laboratory, Yale University School of Medicine RCV000087173 SCV000155138 probable-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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