ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.542G>A (p.Arg181His) (rs397514495)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131382 SCV000186358 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),Well-characterized mutation at same position
Color RCV000131382 SCV000686749 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-09 criteria provided, single submitter clinical testing
Counsyl RCV000576528 SCV000677774 likely pathogenic Li-Fraumeni syndrome 1 2017-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000255239 SCV000322072 likely pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted TP53 c.542G>A at the cDNA level, p.Arg181His (R181H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg181His has been reported in several individuals with early-onset breast cancer, another with prostate cancer, and a woman with adrenocortical carcinoma, pheochromocytoma, and glioblastoma multiforme all diagnosed after age 50 who was reported to also carry a diagnosis of Neurofibromatosis type 1 (B?rresen 1992, Heymann 2010, Raymond 2013, Tung 2015). Functional assays evaluating transactivation, DNA binding, and growth suppression have demonstrated mixed results (Malcikova 2010, Monti 2011, Hekmat-Scafe 2016, Kotler 2018) consistent with this variant being reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). However, TP53 Arg181His has been shown to be defective in promoter binding and transactivation specifically of apoptotic target genes, with a consequent impact on apoptotic activity observed (Flaman 1998, Campomenosi 2001, Monti 2007, Schlereth 2010, Monti 2011). TP53 Arg181His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding 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 currently available evidence, we consider this to be a likely pathogenic variant; however, based on published case reports, it may not result in classic Li-Fraumeni syndrome.
Invitae RCV000168247 SCV000218918 pathogenic Li-Fraumeni syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 181 of the TP53 protein (p.Arg181His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs397514495, ExAC 0.003%). This variant has been reported in an individual with breast cancer and a strong family history of breast cancer, leiomyosarcoma, and other neoplasms (PMID: 1591732, 1631137), a 29 year old with early-onset breast cancer and family history of multiple cancers (PMID: 21059199), and an individual affected with adrenocortical carcinoma and a contralateral pheochromocytoma also clinically diagnosed with neurofibromatosis type 1 (PMID: 23175693). ClinVar contains an entry for this variant (Variation ID: 142320). Experimental studies indicate that this missense change disrupts protein function (PMID: 20128691, 21343334, 11429705). Three different missense changes involving this codon (p.Arg181Cys, p.Arg181Leu, p.Arg181Pro) have been reported in individuals with TP53-related conditions (PMID: 1581912, 8308926, 15925506), suggesting that the arginine residue is clinically important. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168247 SCV000731671 likely pathogenic Li-Fraumeni syndrome 2017-11-06 criteria provided, single submitter clinical testing The p.Arg181His variant in TP53 has been observed as a germline variant in 4 ind ividuals with Li-Fraumeni syndrome (LFS) related cancers (Borresen 1992, Heyman 2010, Raymond 2013). In two of these individuals, the reported age at diagnosis was significantly older than what is typically observed for LFS (median age at d iagnosis = 25, Schneider 2013; GeneReviews). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 142320) and has been id entified in 3/111577 European chromosomes by the genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org; dbSNP rs397514495). In vitro functional transactivation assays provide some evidence that the p.Arg181His is temperature -sensitive and may impact protein function (Soussi 2005, Monti 2011, Malcikova 2 010). Three different missense changes at the same position (p.Arg181Cys, p.Arg1 81Leu, p.Arg181Pro) have been reported in individuals with TP53-related conditio ns (Sidransky 1992, Kyritsis 1994, Krutilkova 2005), supporting that a change at this position is not tolerated. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Arg181His variant is l ikely pathogenic.

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