ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.329G>C (p.Arg110Pro)

dbSNP: rs11540654
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222678 SCV000278043 pathogenic Hereditary cancer-predisposing syndrome 2023-07-17 criteria provided, single submitter clinical testing The p.R110P pathogenic mutation (also known as c.329G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 329. The arginine at codon 110 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in two male individuals from separate families with Li-Fraumeni syndrome, one with gastric cancer at 32 years of age, and the other with two primary sarcomas at 37 and 44 years of age (Mitchell G et al. PLoS ONE. 2013; 8(7):e69026; Masciari S et al. Genet. Med. 2011 Jul; 13(7):651-7). This variant has also been reported and confirmed de novo in an individual with 2 soft tissue sarcomas, diagnosed at age 38 years and 44 years (Renaux-Petel M et al. J. Med. Genet. 2018 Mar;55(3):173-180). Multiple functional studies have demonstrated that this alteration is deficient in transcriptional activation, DNA binding, and induction of apoptosis (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000231991 SCV000285189 pathogenic Li-Fraumeni syndrome 2023-09-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 110 of the TP53 protein (p.Arg110Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with classical Li-Fraumeni syndrome (LFS) (PMID: 21552135, 23894400, 29070607; Invitae). ClinVar contains an entry for this variant (Variation ID: 233627). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 23897043, 24076587). This variant disrupts the p.Arg110 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16778209, 21445056, 24076587; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000222678 SCV002582614 pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288889 SCV002583175 pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462528 SCV004206240 pathogenic Adrenocortical carcinoma, hereditary 2023-08-25 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV002288889 SCV004932477 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24076587, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21552135, 23894400, 29070607].

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