ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.31G>C (p.Glu11Gln) (rs201382018)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000161016 SCV000214035 likely benign Hereditary cancer-predisposing syndrome 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Other data supporting benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034640 SCV000043504 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000161016 SCV000910740 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
GeneDx RCV000213044 SCV000211732 likely benign not specified 2017-08-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000213044 SCV000918326 uncertain significance not specified 2018-02-02 criteria provided, single submitter clinical testing Variant summary: TP53 c.31G>C (p.Glu11Gln) results in a conservative amino acid change located in the p53 transactivation domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 16.091 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.31G>C has been reported in the literature predominantly in East Asian individuals affected with various cancer types including myelodysplastic/myeloproliferative disease, breast cancer, ovarian cancer and Lynch syndrome, without strong evidence for causality. One reported functional study showed the variant to result in drastic alteration of the p53 transcriptional activity (~70% residual activity), similar to that observed with well characterized dominant-negative missense mutations suggesting that it might be a bona fide dominant-negative mutation (Zerdoumi_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar with conflicting classifications (VUS, likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign, until additional clinical and functional evidence becomes available.
Invitae RCV000226569 SCV000285187 uncertain significance Li-Fraumeni syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 11 of the TP53 protein (p.Glu11Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs201382018, ExAC 0.05%). This variant has been reported in an individual with childhood myelodysplastic/myeloproliferative disease, an individual with acute myeloid leukemia, an individual with suspected Lynch syndrome, and two individuals with breast cancer, as well as unaffected control individuals (PMID: 22571758, 24724063, 25980754, 28724667, 22703879). ClinVar contains an entry for this variant (Variation ID: 41723). Experimental studies have shown that this variant does not affect transactivational activity of the TP53 protein in yeast assays (PMID: 12826609), but increases its aggregation propensity in vitro (PMID: 18199664). However, the clinical significance of the latter is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000213044 SCV000731481 uncertain significance not specified 2017-03-13 criteria provided, single submitter clinical testing The p.Glu11Gln variant in TP53 has been reported as a somatic variant in breast, lung, prostate, and colorectal cancers (COSMIC database, http://cancer.sanger.a c.uk/cosmic) and as a germline variant in 3 individuals with a variety of cancer s, including Lynch-syndrome associated cancers, intracranial germ cell tumors, a nd myelodysplastic/myeloproliferative disease (Ismael 2012, Wang 2014, Yurgelun 2015). Ismael et al. reported the variant in a child with myelodysplastic diseas e but also in the mother and two sisters. The authors do not provide clinical da ta for these relatives but this finding raises suspicion that the variant may no t cause disease. This variant has also been reported in ClinVar (Variation ID 41 723). It has also been identified in 4/8534 of East Asian chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201382 018). Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, the clinical s ignificance of the p.Glu11Gln variant is uncertain.
Mendelics RCV000226569 SCV000839129 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing

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