ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.388C>G (p.Leu130Val)

dbSNP: rs863224683
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536061 SCV000629818 uncertain significance Li-Fraumeni syndrome 2023-04-11 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20407015). 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. ClinVar contains an entry for this variant (Variation ID: 458543). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 130 of the TP53 protein (p.Leu130Val).
Ambry Genetics RCV000565366 SCV000672400 pathogenic Hereditary cancer-predisposing syndrome 2021-08-09 criteria provided, single submitter clinical testing The p.L130V pathogenic mutation (also known as c.388C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 388. The leucine at codon 130 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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). 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 alteration has been observed numerous times as a somatic mutation in the database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759374 SCV000888665 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000565366 SCV002582093 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289731 SCV002582656 uncertain significance Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV003459202 SCV004206212 likely pathogenic Adrenocortical carcinoma, hereditary 2023-10-23 criteria provided, single submitter clinical testing

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