ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.394A>C (p.Lys132Gln)

dbSNP: rs747342068
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001205860 SCV001377139 uncertain significance Li-Fraumeni syndrome 2019-09-09 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect TP53 protein function (PMID: 12826609). This variant has been observed in an individual affected with TP53-related conditions (PMID: 18989156). ClinVar contains an entry for this variant (Variation ID: 376628). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 132 of the TP53 protein (p.Lys132Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine.
Baylor Genetics RCV003463827 SCV004206273 likely pathogenic Adrenocortical carcinoma, hereditary 2023-05-30 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004022226 SCV004931082 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 21188122, 25961455, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18989156].
Ambry Genetics RCV004678695 SCV005177912 pathogenic Hereditary cancer-predisposing syndrome 2024-04-05 criteria provided, single submitter clinical testing The p.K132Q pathogenic mutation (also known as c.394A>C), located in coding exon 4 of the TP53 gene, results from an A to C substitution at nucleotide position 394. The lysine at codon 132 is replaced by glutamine, an amino acid with similar properties. This variant has been reported in a child with a personal history of adrenocortical carcinoma diagnosed at 18 months and osteosarcoma diagnosed at age 11 (Delaney HM et al. J Pediatr Hematol Oncol, 2008 Nov;30:803-6). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another variant at the same codon, p.K132R (c.395A>G), has been reported in medulloblastoma and breast cancer cohorts (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Waszak SM et al. Lancet Oncol., 2018 06;19:785-798; Yi D et al. Hum. Genomics, 2019 01;13:4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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