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

gnomAD frequency: 0.00018  dbSNP: rs145151284

Total submissions: 15

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	This alteration is classified as likely benign based on a combination of the following: 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.
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	2024-01-31	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	benign	Li-Fraumeni syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	likely benign	not provided	2020-10-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000213063	SCV002011360	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001260345	SCV002065367	benign	not specified	2021-06-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129462	SCV002532728	benign	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411116	SCV004017855	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003935214	SCV004759603	likely benign	TP53-related condition	2020-11-30	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).