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

dbSNP: rs201382018

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034640	SCV000211732	likely benign	not provided	2021-12-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24896186, 28251968, 21380628, 30840781, 22703879, 25846456, 23973262, 25980754, 27545002, 28466600, 22571758, 28369373, 18199664, 28724667, 28472496, 12826609, 31321604, 30224644, 11397945, 15510160, 33257846, 30936070, 32941702, 34478609, 34736091, 34069252)
Ambry Genetics	RCV000161016	SCV000214035	likely benign	Hereditary cancer-predisposing syndrome	2019-02-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226569	SCV000285187	likely benign	Li-Fraumeni syndrome	2023-12-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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
Color Diagnostics, LLC DBA Color Health	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	2024-05-21	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 0.00012 in 1613940 control chromosomes, predominantly at a frequency of 0.0042 within the East Asian subpopulation in the gnomAD database (v4.1.0), including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 106 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05). A recent report assessing population prevalence estimates of germline TP53 variants based on a gnomAD-based analysis classified this variant as likely benign (e.g., 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 (e.g., 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 (e.g., Zerdoumi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 26527317, 25846456, 23973262, 27545002, 28369373, 30352134, 31666926, 12826609, 18199664). ClinVar contains an entry for this variant (Variation ID: 41723). 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 ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, 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.
Sema4, Sema4	RCV000161016	SCV002530447	likely benign	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213044	SCV002760893	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924896	SCV004744566	likely benign	TP53-related disorder	2022-11-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
GenomeConnect - Invitae Patient Insights Network	RCV000226569	SCV004228759	not provided	Li-Fraumeni syndrome		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 04-16-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.