ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.31G>C (p.Glu11Gln) (rs201382018)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000161016 SCV000214035 likely benign Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000226569 SCV000285187 likely benign Li-Fraumeni syndrome 2020-11-21 criteria provided, single submitter clinical testing
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 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,; 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
Color Health, Inc RCV000161016 SCV000910740 likely benign Hereditary cancer-predisposing syndrome 2016-06-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213044 SCV000918326 likely benign not specified 2020-09-25 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 variant allele was found at a frequency of 5.2e-05 in 250748 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. A recent report assessing population prevalence estimates of germline TP53 variants based on a gnomAD-based analysis classified this variant as likely benign (Andrade_2019). 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, gastric cancer and Lynch syndrome, without strong evidence for causality (example, Yurgelun_2015, Lee_2015, Takenaka_2015, Uji_2014, Yamaguchi_2016, Zerdoumi_2017, Terashima_2019). 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. The most pronounced variant effect results in 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). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (5x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034640 SCV001134866 likely benign not provided 2019-01-25 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030742 SCV001193758 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV001124310 SCV001283247 uncertain significance Li-Fraumeni syndrome 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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.

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