ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1010G>A (p.Arg337His) (rs121912664)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413754 SCV000492466 pathogenic Neoplasm of the breast criteria provided, single submitter research
Ambry Genetics RCV000128923 SCV000172792 pathogenic Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Color RCV000128923 SCV000537678 pathogenic Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing
Counsyl RCV000576817 SCV000677744 pathogenic Li-Fraumeni syndrome 1 2017-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000481814 SCV000568754 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.1010G>A at the cDNA level, p.Arg337His (R337H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg337His is known to be a disease-causing founder variant in Southern Brazil, present in 0.2-0.3% of the population (Garritano 2010). Initially, this variant was thought to predispose carriers primarily to childhood adrenocortical carcinoma (ACC) (Latronico 2001, Ribeiro 2001). However, more recently it has been identified in families with a broader tumor spectrum, with several meeting criteria for Li-Fraumeni-like (LFL) syndrome, but fewer meeting Li-Fraumeni syndrome clinical diagnostic criteria (Figueiredo 2006, Assumpcao 2008, Custodio 2011, Gomes 2012, Silva 2012, Custodio 2013, Giacomazzi 2013, Giacomazzi 2014, Seidinger 2015, Achatz 2016). Mastellaro et al. (2017) reported a 21% cumulative risk of cancer by age 45 in carrier relatives of probands ascertained due to a diagnosis of adrenocortical tumor. Loss of heterozygosity has been observed in breast cancer, adrenocortical carcinoma, choroid plexus carcinoma, and osteosarcoma, suggesting this variant played a role in tumorigenesis (Latronico 2001, Ribeiro 2001, Assumpcao 2008, de Oliveira Lima 2011, Custodio 2011, Seidinger 2011, Herrmann 2012). DiGiammarino et al. (2002) demonstrated that TP53 Arg337His introduces a pH sensitivity into the p53 protein, affecting stability of the tetramerization domain. While some in vitro based functional assays have shown this variant to have partially functional to almost normal transactivation activity (Lomax 1998, Ribeiro 2001, Kato 2003), Jordon et al. (2010) observed that TP53 Arg337His required higher levels of protein expression to initiate transactivation, likely due to its reduced ability to form tetramers, and resulted in overall reduced transactivation. TP53 Arg337His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the tetramerization domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the current evidence, we consider TP53 Arg337His to be pathogenic; however based on published literature, it may result in higher risk for adrenocortical carcinoma and lower risk for other cancers associated with classic Li-Fraumeni syndrome.
Invitae RCV000197240 SCV000253848 pathogenic Li-Fraumeni syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 337 of the TP53 protein (p.Arg337His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121912664, ExAC 0.009%). This variant has been reported in affected individuals and has been shown to segregate with disease in families affected with multiple types of cancer (PMID: 10864200, 16033918, 16494995, 21192060). It was reported to have a frequency of 0.13% in one large study (n=171,649) performed on a Brazilian newborn population (PMID: 23733769). ClinVar contains an entry for this variant (Variation ID: 12379). This variant has been estimated to have a penetrance of 9.9% for childhood adrenocortical carcinoma (PMID: 16033918). Studies of cancer-prone families with this variant show that individual risk of cancer is highly variable, and adult carriers who are not affected by cancer have been identified, suggesting that there is age-dependent (and possibly incomplete) penetrance (PMID: 19717094). Experimental studies using model organisms and mammalian cells have shown that this missense change can partially disrupt TP53 protein function (PMID: 20407015, 12826609, 9704930). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000481814 SCV000692060 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000197240 SCV000839103 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000013178 SCV000033425 pathogenic Adrenocortical carcinoma, pediatric 2006-01-01 no assertion criteria provided literature only

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