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

gnomAD frequency: 0.00003  dbSNP: rs371524413

Total submissions: 16

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	2023-06-14	criteria provided, single submitter	clinical testing	Reported in individuals with Li-Fraumeni spectrum tumors, but some had other TP53 variants identified as well, making it difficult to assess the individual contribution of TP53 Arg156His to their phenotype; in addition this variant was also identified in unaffected relatives and controls (Quesnel et al., 1999; Heymann et al., 2010; Juhlin et al., 2015; DiNardo et al., 2016; Andrade et al., 2017; Stjepanovic et al., 2018; Momozawa et al., 2018; Maxwell et al., 2021; Dorling et al., 2021); Published functional studies are inconclusive: partial or no impact on transcriptional activation and growth suppression (Quesnel et al., 1999; Kato et al., 2003; Monti et al., 2011; Giacomelli et al., 2018; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11793474, 21343334, 25637381, 27923552, 28477317, 30709875, 31948886, 17606709, 15580553, 17133269, 9667734, 25490274, 17318340, 27146902, 17541742, 27210295, 29077256, 29979965, 28861920, 28152038, 25299233, 21348641, 10519380, 17311302, 12826609, 30092803, 25184754, 26086041, 21666498, 30089713, 21059199, 30720243, 30840781, 30306255, 29625052, 31105275, 32998877, 33257846, 10435620, 33932062, 15781620, 35371985, 26230955, 34273903, 30352134, 27463065, 30327374, 27276561, 27895058, 26585234, 22186996, 16818505, 23246812, 21519010, 20407015, 11782540, 30224644, 15510160, 32566746, 30816478, 27959731, 25952993, 22915647, 34863587, 30287823, 36451132, 35306447, 35709138, 33471991)
Ambry Genetics	RCV000115722	SCV000186315	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-29	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	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 156 of the TP53 protein (p.Arg156His). This variant is present in population databases (rs371524413, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of TP53-related conditions and/or TP53-related conditions (PMID: 9667734, 10435620, 21343334, 26086041, 27210295, 28477317, 30092803; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 10435620, 12826609, 17311302, 17606709, 21343334, 29979965, 30224644). 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 Diagnostics, LLC DBA Color Health	RCV000115722	SCV000911005	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 156 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A different variant affecting the same codon, c.467G>C (p.Arg156Pro), is considered to be disease-causing by one external laboratory (ClinVar variation ID: 634768), suggesting that Arg or similar amino acid at this position is important for the protein function. Functional studies in yeast and mammalian cells reported this variant protein to be partially functional to normal (PMID: 10435620, 12826609, 15781620, 21343334, 29979965, 30224644 and the IARC database). This variant has been reported in individuals with Li-Fraumeni syndrome with one or more additional TP53 missense covariants (PMID: 9667734, 10435620), Li-Fraumeni syndrome meeting Chompret criteria, astrocytoma, pediatric sarcoma (Nehoray et al, ASCO 2022), colorectal cancer (PMID: 26086041, 30092803, 30306255), breast cancer (PMID: 30287823, 31105275, 33471991; Nehoray et al, ASCO 2022) and in control individuals (PMID: 33471991). This variant has been identified in 4/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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 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	2024-01-22	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. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 30306255, 27210295, 27895058, 16818505, 11782540, 22915647, 21059199, 26230955, 21519010, 20407015, 25490274, 27463065, 30327374, 30287823, 17606709, 21343334, 26585234, NCCN_AML, NCCN_MDS, NCCN_MPN, 25952993, 27276561, 17311302, 10435620, 31105275, 22186996, 27680515, 30092803, 30709875, 27959731, 30352134). ClinVar contains an entry for this variant (Variation ID: 127811). 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
Sema4, Sema4	RCV000115722	SCV002530461	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272128	SCV002556430	uncertain significance	Familial cancer of breast	2020-06-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467059	SCV004206217	uncertain significance	Adrenocortical carcinoma, hereditary	2023-10-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213052	SCV004242761	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148908	SCV000190654	likely benign	Li-Fraumeni syndrome	2014-06-01	no assertion criteria provided	research