ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.467G>A (p.Arg156His) (rs371524413)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV001293017 SCV001481787 uncertain significance Li-Fraumeni syndrome 1 2021-02-22 reviewed by expert panel curation This variant has been reported in 4 probands meeting Revised Chompret criteria (PS4_Supporting; Internal laboratory and clinical contributors, SCV000186315.7). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor, SCV000186315.7). Transactivation assays show a partially functional variant 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_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.467G>A (p.Arg156His) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_moderate; BS2_supporting; BS4_supporting.
GeneDx RCV000656987 SCV000149631 uncertain significance not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.467G>A at the cDNA level, p.Arg156His (R156H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Although this variant has been reported in at least two individuals with multiple Li-Fraumeni spectrum tumors, both had other TP53 variants identified as well, making it difficult to assess the individual contribution of TP53 Arg156His to their phenotype (Quesnel 1999, DiNardo 2016). This variant was also observed in a woman with early-onset bilateral breast cancer (Heymann 2010) and a teenage patient with adrenocortical carcinoma (Juhlin 2015). On functional interrogation TP53 Arg156His was not found to impact transcriptional activation or growth suppression (Quesnel 1999, Monti 2011) and is 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). TP53 Arg156His was not observed at a significant frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg156His is located in 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 currently available information, it is unclear whether TP53 Arg156His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115722 SCV000186315 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-09 criteria provided, single submitter clinical testing The p.R156H variant (also known as c.467G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 467. The arginine at codon 156 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in the germline of a 17-year-old female with adrenocortical carcinoma (Juhlin CC et al. J. Clin. Endocrinol. Metab. 2015 Mar;100(3):E493-502). Additionally, this alteration was detected in the germline of a severely affected child with Li-Fraumeni syndrome (LFS) who also harbored two additional TP53 alterations and had a maternal family history consistent with LFS. Individual analysis of the two alterations found in cis (p.R156H and p.R267Q) showed only weak mutant phenotypes in functional studies, whereas the double mutant showed complete loss of transactivation activity and growth suppression. Authors suggest that p.R156H may cause a partial defect, with a second alteration needed on the same allele to fully inactivate the protein (Quesnel S et al. Oncogene. 1999 Jul;18(27):3970-8; Soussi T et al. Hum. Mutat. 2005 Jan;25(1):6-17). This same combination of variants (p.R156H and p.R267Q) was observed in a male diagnosed with sarcoma at age 40 and acute myeloid leukemia at age 42 (Swaminathan M et al. Cold Spring Harb Mol Case Stud 2019 02;5(1). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional or wild type-like transactivation activity in two different yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-279). Additional studies conducted in human cell lines show retained growth suppression (Kotler E et al. Mol.Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration has been observed in numerous individuals who do not have a personal or family history that is consistent with or suggestive of TP53-associated disease (Ambry internal data). Based on the available evidence to date, the clinical significance of this alteration remains unclear.
Invitae RCV000148908 SCV000218877 uncertain significance Li-Fraumeni syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 156 of the TP53 protein (p.Arg156His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371524413, ExAC 0.006%). This variant was observed in individuals affected with Li-Fraumeni syndrome (LFS) (PMID: 9667734, 10435620, 26086041, 21343334), an individual affected with fibrolamellar hepatocellular carcinoma and this individual's unaffected mother (PMID: 28477317), an individual with colon cancer (PMID: 30092803), and an individual affected with rhabdomyosarcoma and therapy-related acute myeloid leukemia (PMID: 27210295). However, in some of these individuals (PMID: 21343334, 27210295, 26086041, 10435620, 9667734), additional missense variants were identified in the TP53 gene, making it challenging to determine the relative contribution of the p.Arg156His missense change to the phenotype. ClinVar contains an entry for this variant (Variation ID: 127811). Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 10435620, 21343334, 17606709, 17311302, 12826609, 30224644, 29979965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213052 SCV000602272 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing
Mendelics RCV000148908 SCV000839119 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115722 SCV000911005 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-17 criteria provided, single submitter clinical testing
Mendelics RCV000989720 SCV001140262 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030737 SCV001193753 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213052 SCV001360864 uncertain significance not specified 2019-08-06 criteria provided, single submitter clinical testing Variant summary: TP53 c.467G>A (p.Arg156His) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the p53 protein. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251268 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.467G>A has been reported in the literature in a family with Li-Fraumeni Syndrome (LFS) spectrum tumors (Quesnel_1999), however additional TP53 variants were also present in the proband (both in cis and trans), and in other family members (in the mother another variant was found in cis). The variant was also reported in a patient affected with rhabdomyosarcoma (diagnosed at age 42), who met the criteria for LFS evaluation; this patient also harbored another co-occurring (phase unknown) TP53 variant (DiNardo_2016, Swaminathan_2019). The variant of interest was also reported (in absence of other variants) in individuals affected with different tumor phenotypes, including e.g. breast, colon, and adrenocortical carcinoma (Heymann_2010, Momozawa_2018, Rana_2019, Bonache_2018, Stjepanovic_2018, Juhlin_2015), however without strong evidence for causality. These data therefore do not allow clear conclusions about variant significance. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated conflicting evidence for functional impact, including decreased protein expression in mammalian cells (Quesnel_1999), and partial (Petitjean_2007), or intact transactivation capacity (Monti_2011) in yeast based assays. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (5x) or Likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV000989720 SCV001450498 likely pathogenic Squamous cell carcinoma of the head and neck criteria provided, single submitter case-control
CSER _CC_NCGL, University of Washington RCV000148908 SCV000190654 likely benign Li-Fraumeni syndrome 2014-06-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.