Submissions for variant NM_000546.6(TP53):c.139C>T (p.Pro47Ser)

gnomAD frequency: 0.00123  dbSNP: rs1800371

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991144	SCV001142551	benign	Li-Fraumeni syndrome	2019-08-28	reviewed by expert panel	curation	This variant has a minor allele frequency of 0.01645 (1.6%, 410/24,922 alleles) in the African subpopulation of the gnomAD cohort (BA1). The variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show supertransactivation 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). Finally, this variant has been observed in at least 105 60+ year old females without a cancer diagnosis (BS2; FLOSSIES database - https://whi.color.com). In summary, TP53 c.139C>T; p.Pro47Ser meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BA1, BP4, BS3, BS2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036530	SCV000060185	uncertain significance	not specified	2011-09-23	criteria provided, single submitter	clinical testing	The Pro47Ser variant in TP53 is a common polymorphism in individuals with Africa n ancestry and has an observed minor allele frequency ranging from 2.2 - 6.7% in Yorubans (HapMap and 1000 Genomes; Felley-Bosco 1993). This polymorphism has a lso been observed in Brazilian and Kashmiri populations with gliomas, bladder an d colorectal cancer (Pinto 2008, Sameer 2010, Santos 2011). Despite the common nature of this polymorphism, there have been extensive functional studies sugges ting the Pro47Ser change has functional consequences and associated with increas ed cancer susceptibility; however, the data and consensus is variable (Olivier 2 010). The proline at position 47 lies adjacent to a functionally important prol ine-rich region (amino acids 64-92) and the adjacent serine at position 46 has b een reported to be an important phosphorylation site necessary for p53-dependent apoptotic activity (Pistritto 2007). Moreover, functional studies suggest the Pro47Ser variant has decreased activity to transactivate downstream apoptotic ef fector molecules (Li 2005; Whibley 2009). Proline at position 47 is poorly cons erved in vertebrate organisms and absent from more distantly related organisms, suggesting a benign role. The variant has never been reported in a family with Li Fraumeni syndrome. Although this variant is a common polymorphism, the clinic al significance of it, particuarly in the homozgyous state, cannot be determined at this time.
GeneDx	RCV000036530	SCV000169027	benign	not specified	2013-10-08	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	RCV000131567	SCV000186571	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Pathway Genomics	RCV000172826	SCV000223792	benign	Li-Fraumeni syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000036530	SCV000230122	benign	not specified	2014-09-29	criteria provided, single submitter	clinical testing
Invitae	RCV000991144	SCV000261827	benign	Li-Fraumeni syndrome	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590436	SCV000605423	benign	not provided	2017-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131567	SCV000686719	benign	Hereditary cancer-predisposing syndrome	2015-08-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590436	SCV000697429	benign	not provided	2017-08-22	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.139C>T (p.Pro47Ser) variant located in the transactivation domain involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a benign outcome for this substitution. his variant was found in 436/277308 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.016374 (393/24002). This frequency is about 412 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, case-control studies also show that this variant does not confer an associated cancer risk. Despite the common nature of this polymorphism, functional studies are inconclusive as to whether the variant has functional consequences. Some studies (Li_ 2005, Rigacci_2008, Jennis_ 2014 and Jennis_2016) have shown that this variant leads to functional impairment, while Wasserman_2015 indicates the variant has an additive affect, suggesting a notion that this variant is a functional polymorphism. The proline at position 47 lies adjacent to a functionally important proline-rich region (amino acids 64-92) and the adjacent serine at position 46 has been reported to be an important phosphorylation site necessary for p53-dependent apoptotic activity. A functional sudy published showed that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (ironmediated nonapoptotic cell death) and that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Based on these observations Jennis_2016 suggested that the S47 variant may contribute to increased cancer risk in individuals of African descent. However, multiple clinical diagnostic laboratories have cited the variant as Benign. Furthermore, the variant of interest has been found to co-occur with multiple pathogenic variants, PTEN c.406T>C (p.Cys136Arg) and BRCA1 c.213-12A>G and likely pathogenic MLH1 variant, c.1731+1G>T (2 individuals). Taken together, their is a discrepancy between the clinical observations (co-occurrence with other pathogenic/likely pathogenic variants, and large excess in the control cohort) and functional data, where a correlation between the measured property and the disease physiology has not been clearly established. Therefore, this variant is classified as "Benign".
PreventionGenetics, part of Exact Sciences	RCV000036530	SCV000806234	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000172826	SCV001282025	benign	Li-Fraumeni syndrome 1	2018-06-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225273	SCV002505078	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV002225273	SCV002515177	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000036530	SCV002760891	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496568	SCV002805659	benign	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2021-10-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149630	SCV003837776	benign	Breast and/or ovarian cancer	2021-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000036530	SCV000086396	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000590436	SCV000692095	benign	not provided	2018-02-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355028	SCV001549786	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Pro47Ser variant was identified in 41 of 5182 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer, brain tumour, gliomas, bladder cancer or Lynch syndrome and was present in 6 of 2858 control chromosomes (frequency: 0.002) from healthy individuals (Alawadi 2011, Almeida 2009, Bodian 2014, Cock-Rada 2017, Pinto 2008, Sameer 2010, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs1800371) as ‚ With Uncertain significance, other allele‚Äù, ClinVar (as benign by GeneDx, Ambry Genetics, Pathway Genomics, EGL Genetic Diagnostics, Invitae, ARUP, Color Genomics, Integrated Genetics, and Mayo Clinic and as uncertain significance by Laboratory for Molecular Medicine), Cosmic (3x found in liver, endometrium and kidney cancer), LOVD 3.0 (1x), and in IARC TP53 (as neutral). The variant was not identified in the Database of germline p53 mutations. The variant was identified in control databases in 433 of 277106 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 393 of 24002 chromosomes (freq: 0.02), Other in 4 of 6464 chromosomes (freq: 0.001), Latino in 30 of 34412 chromosomes (freq: 0.001), European in 4 of 126662 chromosomes (freq: 0.00003), and South Asian in 2 of 30780 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, and Finnish populations. The p.Pro47 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The Pro47Ser polymorphism has a significant influence on p53 function, by reducing phosphorylation on serine 46 and impairing p53 apoptotic and transcriptional functions (Olivier 2010, Li 2005) in mouse embryo fibroblasts (Basu 2016,). The functional study of the p53 transactivation domain aggregates in vitro showed aggregation propensity of the Pro47Ser mutated peptide have the same rate as the wild type (Rigacci 2008). In another study (Cock-Rada 2017) the variant was identified with a co-occurring pathogenic BRCA1 variant, suggesting the Pro47Ser variant may not have clinical significance. Association of Pro47Ser polymorphism was not observed in bladder (Santos 2011), gliomas (Pinto 2008), colorectal cancer (Sameer 2010), and breast cancer (Alawadi 2011, Sharma 2014). In addition, the meta-analysis of 11 case-control studies by Chandel (2013) concluded that published results seem to be driven by technical artifacts rather than justified biological effects. This systematic review and meta-analysis of genetic association studies shows that TP53 p.Pro47Ser is unlikely to be a major risk factor for different types of cancers and many diseases. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131567	SCV001950168	benign	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing