ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.949C>T (p.Gln317Ter) (rs764735889)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000583201 SCV000691666 pathogenic Hereditary cancer-predisposing syndrome 2017-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000520579 SCV000618916 likely pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing This apparently mosaic variant is denoted TP53 c.949C>T at the cDNA level and p.Gln317Ter (Q317X)at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stopcodon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation ornonsense-mediated mRNA decay. This variant has not, to our knowledge, been published in the literature as a germlinevariant; however, it has been reported as a somatic variant in several tumor types including bladder, oral squamouscell, and ovarian (Concin 2005, Dekairelle 2005, Hassan 2008). One functional study found that this variantsignificantly impacted transactivation activity (Dekairelle 2005). We consider this variant to be likely pathogenic
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000615397 SCV000731540 pathogenic Li-Fraumeni syndrome 2017-06-30 criteria provided, single submitter clinical testing The p.Gln317X variant in TP53 has not been previously reported in individuals wi th Li-Fraumeni syndrome or in large population studies. This nonsense variant le ads to a premature termination codon at position 317, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gen e is an established disease mechanism in individuals with Li-Fraumeni syndrome. In summary, this variant meets criteria to be classified as pathogenic for Li-Fr aumeni syndrome in an autosomal dominant manner based on predicted impact to the protein and absence in controls.

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