ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.752T>G (p.Ile251Ser) (rs730882027)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161070 SCV000211804 likely pathogenic not provided 2015-09-23 criteria provided, single submitter clinical testing This variant is denoted TP53 c.752T>G at the cDNA level, p.Ile251Ser (I251S) at the protein level, and results in the change of an Isoleucine to a Serine (ATC>AGC) in exon 7. Since Isoleucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ile251Ser alters a position that is highly conserved among mammals and is located in the DNA binding domain (UniProt). TP53 Ile251Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this variant has not been reported as a germline variant to our knowledge, it has been seen as a somatic mutation in multiple tumor types, including: lymphoid and haemopoietic, breast, ovary, central nervous system, and small intestine (COSMIC). Other published conservative substitutions in the same codon (TP53 p.Ile251Leu and TP53 p.Ile251Met) are considered pathogenic based on reports of association with Li-Fraumeni or Li-Fraumeni-like syndromes and functional analyses showing partial loss of TP53 function (Kato 2003, Monti 2007, Wu 2011, Malcikova 2010, Monti 2011, IARC TP53 database). In silico analyses predict that TP53 Ile251Ser is probably damaging to protein structure and function. Based on the currently available information, we consider TP53 Ile251Ser to be an expected pathogenic variant. Mosaicism for TP53 mutations has been reported in at least three patients, all of whom had cancer themselves and none of whom had a family history significant for Li Fraumeni syndrome (Prochazkova 2009, Walsh 2011, Mitchell 2013). This variant has been seen apparently mosaic. The variant is found in ENDOM-HEREDIC panel(s).

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