ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.145G>C (p.Asp49His) (rs587780728)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123095 SCV000166395 uncertain significance Li-Fraumeni syndrome 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 49 of the TP53 protein (p.Asp49His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs587780728, ExAC 0.01%). This variant has been reported in individuals affected with clinical features of Li-Fraumeni syndrome, and several other individuals with family histories of cancer, but CN517202 fulfilling the criteria for Li-Fraumeni or Li-Fraumeni-like syndromes (PMID: 27545002, 28861920, 28902083). ClinVar contains an entry for this variant (Variation ID: 135948). Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein (PMID: 12826609) and increases VEGF expression (PMID: 12901974). In addition, two studies have shown that in combination with p.Asp48His, this variant affects TP53 binding to RPA (PMID: 9207066, 15489903) and homologous recombination suppression (PMID: 15489903), but the effect of this variant alone on these aspects of TP53 function has not been tested, therefore the clinical significance of these results are unknown. 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.
Ambry Genetics RCV000129275 SCV000184035 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000410497 SCV000488754 uncertain significance Li-Fraumeni syndrome 1 2016-06-07 criteria provided, single submitter clinical testing
Color RCV000129275 SCV000686722 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-20 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030740 SCV001193756 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000410497 SCV001282023 uncertain significance Li-Fraumeni syndrome 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV001192616 SCV001360862 uncertain significance not specified 2019-03-14 criteria provided, single submitter clinical testing Variant summary: TP53 c.145G>C (p.Asp49His) results in a non-conservative amino acid change located in the transactivation domain 2 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246194 control chromosomes (gnomad). This variant has been reported in the literature in individuals affected with Li-Fraumeni Syndrome and other cancers (Yamaguchi_2016, Yamazaki_2018, Ohmoto_2018). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Narendran_2003). The transfection experiment demonstrated the ability of p.Asp49His to increase the expression of VEGF. However, the association between this effect to Li-Fraumeni Syndrome is not clear. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.

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