ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1079G>C (p.Gly360Ala) (rs35993958)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000991145 SCV001142552 likely benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a minor allele frequency of 0.0005091 (0.05%, 18/35,358 alleles) in the Latino subpopulation of the gnomAD cohort (BS1). This variant also has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, TP53 c.1079G>C; p.Gly360Ala meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BP4, BS3_Supporting.
Ambry Genetics RCV000130776 SCV000185669 likely benign Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
GeneDx RCV000254695 SCV000211767 likely benign not specified 2018-01-02 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.
Invitae RCV000991145 SCV000218979 likely benign Li-Fraumeni syndrome 2020-12-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254695 SCV000602260 benign not specified 2015-06-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254695 SCV000697424 likely benign not specified 2020-11-24 criteria provided, single submitter clinical testing Variant summary: TP53 c.1079G>C (p.Gly360Ala) results in a non-conservative amino acid change in 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 0.00019 in 250440 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 13 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. c.1079G>C has been reported in the literature in individuals affected with different tumor phenotypes, including colorectal cancer, acute lymphoblastic leukemia, breast cancer and osteosarcoma (e.g. Tung_2015, Yorczyk_2015, Zhang_2015, Yurgelun_2017, Qian_2018, Sheng_2019). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2299delA, p.Ser767AlafsX25; in an internal LCA sample), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant protein to confer functional properties such as DNA binding activity, activation of target genes and induction of apoptosis that are similar to wild type TP53 (Wang_2014). Ten other submitters, including an expert panel (ClinGen TP53 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (8x; including the expert panel) or benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000663262 SCV000786491 likely benign Li-Fraumeni syndrome 1 2018-05-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586942 SCV000806232 likely benign not provided 2017-09-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130776 SCV000910695 benign Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000663262 SCV001431510 likely benign Li-Fraumeni syndrome 1 2020-08-07 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000991145 SCV001439184 likely benign Li-Fraumeni syndrome 2020-09-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586942 SCV001501155 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing

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