ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.935C>G (p.Thr312Ser) (rs145151284)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000204899 SCV001142529 benign Li-Fraumeni syndrome 2019-09-16 reviewed by expert panel curation This variant has an allele frequency of 0.0003605 (0.03%, 9/24,966 alleles) in the African 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). Additionally, transactivation assays show retained function 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; PMID: 12826609, 30224644). In summary, TP53 c.935C>G; p.Thr312Ser meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BP4, BS3.
Ambry Genetics RCV000129462 SCV000184232 likely benign Hereditary cancer-predisposing syndrome 2019-02-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000213063 SCV000211763 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.935C>G at the cDNA level, p.Thr312Ser (T312S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has been observed in at least one individual with a personal and/or family history suggestive of Li-Fraumeni syndrome (Bougeard 2008). Additionally, TP53 Thr312Ser has been identified in an individual with a head and neck cancer and in an individual with pancreatic cancer (Mafune 2015, Yang 2016). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Thr312Ser was observed at an allele frequency of 0.029% (7/24028) in individuals of African ancestry in large population cohorts (Lek 2016). TP53 Thr312Ser is not located within a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Thr312Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204899 SCV000261663 likely benign Li-Fraumeni syndrome 2020-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000411116 SCV000488345 uncertain significance Li-Fraumeni syndrome 1 2016-03-03 criteria provided, single submitter clinical testing
Mendelics RCV000204899 SCV000839106 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129462 SCV000910895 likely benign Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213063 SCV001134881 uncertain significance not provided 2020-04-09 criteria provided, single submitter clinical testing
Mendelics RCV000989705 SCV001140244 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411116 SCV001286580 likely benign Li-Fraumeni syndrome 1 2018-01-12 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260345 SCV001437278 benign not specified 2020-09-04 criteria provided, single submitter clinical testing Variant summary: TP53 c.935C>G (p.Thr312Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251488 control chromosomes. The observed variant frequency is approximately 1.7 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 benign. At least one functional study showed this variant has transcriptional activity similar to wild-type (PHANTM database). Nine clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (bening/likely benign n=4, including the expert panel; VUS n=6). Based on the evidence outlined above, the variant was classified as benign.

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