ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.473G>A (p.Arg158His) (rs587782144)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130708 SCV000185595 pathogenic Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Color RCV000130708 SCV000537627 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000496787 SCV000785720 likely pathogenic Li-Fraumeni syndrome 1 2017-11-15 criteria provided, single submitter clinical testing
GeneDx RCV000255654 SCV000322153 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.473G>A at the cDNA level, p.Arg158His (R158H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in multiple individuals meeting Li-Fraumeni diagnostic or Chompret criteria (Varley 1999, Ruijs 2010, Mitchell 2013, Raymond 2013, Wong 2014, Bougeard 2015, Villani 2016) and others with Li-Fraumeni-spectrum cancers (Melhem-Bertrandt 2012, Qian 2018). TP53 Arg158His has also been identified in individuals whose personal histories are inconsistent with Li-Fraumeni syndrome (Robertson 2010, Ceelen 2011), leading Bougeard et al. (2015) to suggest this variant might cause reduced penetrance of Li-Fraumeni-related tumors apart from adrenocortical carcinoma, similar to the TP53 Arg337His Brazilian founder variant. Functional studies have produced variable results. The International Agency for Research on Cancer TP53 database lists TP53 Arg158His as having non-functional transactivation activity based on assays by Kato et al. (2003), consistent with the strong impact on transactivation reported by Smith et al. (1999), while higher levels of transactivation and no dominant-negative effect have been reported in other studies (Campomenosi 2001, Monti 2011, Wasserman 2015). Additionally, cells transfected with TP53 Arg158His demonstrated intermediate levels of growth suppression and colony reduction in comparison to wild-type or other pathogenic variants (Smith 1999, Wasserman 2015, Kotler 2018). TP53 Arg158His was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Arg158His to be pathogenic.
Invitae RCV000227859 SCV000285199 pathogenic Li-Fraumeni syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 158 of the TP53 protein (p.Arg158His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587782144, ExAC 0.002%). This variant has been reported in individuals affected with TP53-related cancers (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693), and in several Li-Fraumeni families (PMID: 20522432, 17606709, 21601526, 18685109). This variant is also known as c.12407G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 141963). Experimental studies using model organisms and mammalian cells have shown that this missense change disrupts TP53 protein function (PMID: 25584008, 21343334, 10229196, 12826609). Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys) have been reported in individuals with TP53-related conditions (PMID: 25234657, 10864200, 22170717, 21339461, 21343334), indicating that this amino acid is important for TP53 function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000227859 SCV000713289 likely pathogenic Li-Fraumeni syndrome 2017-10-20 criteria provided, single submitter clinical testing The p.Arg158His variant in TP53 has been reported in > 17 individuals with Li-Fr aumeni syndrome (LFS)-associated cancers and segregated with disease in at least 5 affected relatives from at least 3 families (Varley 1999, Tabori 2007, Ruijs 2010, Villani 2011, Raymond 2013, Wong 2014, Bougeard 2015, Wasserman 2015, IARC TP53 database: It has also been identified in several una ffected adult relatives (Tabori 2007, Villani 2011, Wong 2014), suggesting reduc ed penetrance for this variant. In vitro functional studies provide some evidenc e that the p.Arg158His variant may impact protein function (Monti 2011, Wasserma n 2015). This variant has also been reported by other clinical laboratories in C linVar (Variation ID: 141963) and has been identified in 1/9844 Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst; dbSNP rs587782144). Additionally, other amino acid changes at this po sition (p.Arg158Cys, p.Arg158Gly, p.Arg158Leu and p.Arg158Pro) have been reporte d in individuals with LFS-associated cancers (Human Gene Mutation Database: Sten son et al., 2017, IARC TP53 database: Bouaoun 2016), suggesting that this amino acid is important for TP53 function. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg158His variant is likely pathogenic. ACMG/AMP Criteria applied: PS4; PM2; PP1; PS3_Supporting ( Richards 2015).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000255654 SCV000692086 pathogenic not provided no assertion criteria provided clinical testing
UCLA Clinical Genomics Center, UCLA RCV000496787 SCV000588155 pathogenic Li-Fraumeni syndrome 1 2013-12-10 criteria provided, single submitter clinical testing

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