ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.949C>A (p.Gln317Lys) (rs764735889)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223439 SCV000274731 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000485421 SCV000569771 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.949C>A at the cDNA level, p.Gln317Lys (Q317K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). Kantorova et al. (2014) observed this variant in an individual with chronic lymphocytic leukemia and concluded that it preserves transcriptional activity in an in vitro-based functional assay. Additionally, TP53 Gln317Lys is reported as functional by in the International Agency for Research on Cancer TP53 database based on transactivation assays completed by Kato et al. (2003). TP53 Gln317Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Gln317Lys occurs at a position that is not conserved and is located within a nuclear localization signal (Shaulsky 1990, Pessoa 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether TP53 Gln317Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000541248 SCV000629890 uncertain significance Li-Fraumeni syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 317 of the TP53 protein (p.Gln317Lys). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs764735889, ExAC 0.003%). This variant has been reported in an individual with chronic lymphocytic leukemia (PMID: 25527155). ClinVar contains an entry for this variant (Variation ID: 231008). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.
Color RCV000223439 SCV000911369 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing

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