ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.974G>T (p.Gly325Val) (rs121912659)

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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 RCV000131411 SCV000186387 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000236768 SCV000293521 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.974G>T at the cDNA level, p.Gly325Val (G325V) at the protein level, and results in the change of a Glycine to a Valine (GGA>GTA). This variant was inherited from an unaffected mother in an individual with non-Hodgkin's lymphoma at age 17 and colon cancer at age 26 (Malkin 1992). Functional studies examining this variant demonstrate slightly decreased binding (Boutell 2004, Malcikova 2010) and partially deficient transactivation activity (Aurelio 2000, Monti 2011); however this variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly325Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Gly325Val occurs at a position that is not conserved and is located in tetramerization domain as well as the region that interacts with CARM1, HIPK1, HIPK2 (Bode 2004, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Gly325Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232570 SCV000285218 uncertain significance Li-Fraumeni syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 325 of the TP53 protein (p.Gly325Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with non-Hodgkin lymphoma and colon carcinoma, and in two relatives that presented with cystic changes in the breast or ovary (PMID: 1565144). ClinVar contains an entry for this variant (Variation ID: 12367). Experimental studies have shown that this missense change can result in reduced DNA binding by TP53 and reduction of apoptosis (PMID: 20128691, 10629033). However, other functional studies report modest or non reduction in TP53 transactivation activity (PMID: 12826609, 21343334, 17606709, 16007150). 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.
OMIM RCV000013165 SCV000033412 pathogenic Non-Hodgkin lymphoma 1992-05-14 no assertion criteria provided literature only
OMIM RCV000013166 SCV000033413 pathogenic Familial colorectal cancer 1992-05-14 no assertion criteria provided literature only

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