ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1010G>A (p.Arg337His) (rs121912664)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128923 SCV000172792 pathogenic Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing The p.R337H pathogenic mutation (also known as c.1010G>A) is located in coding exon 9 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 1010. The arginine at codon 337 is replaced by histidine, an amino acid with highly similar properties. There currently exists a relatively extensive body of literature regarding this alteration. It has been detected at high frequency in Brazilian LFS families and is highly associated with a common haplotype, providing strong evidence of a founder effect in this population (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). Ribeiro and colleagues described p.R337H as a low-penetrance mutation, primarily associated with adrenal cortical tumor risk in childhood; another study identified this mutation at a high (12.1%) frequency in Brazilian women with early-onset breast cancer (Ribeiro RC et al. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9330-5; Giacomazzi J et al, PLoS ONE 2014 ; 9(6):e99893). Other studies have led authors to conclude that the lifetime cancer risks for carriers of this mutation are similar to those of other LFS families, although p.R337H-associated cancers tend to occur with a later age of onset (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). Families with this mutation have been reported with a wide spectrum of tumors including, but not limited to, breast cancers, brain cancers, soft tissue sarcomas, and adrenocortical carcinoma (Achatz et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Borges LM and Avres FM. Genet Mol Res. 2015 Dec 16;14(4):17034-43; IARC Database; Andrade RC et al. Fam. Cancer. 2017 Apr;16(2):243-248; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). One functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). In addition, this amino acid substitution occurs within the protein tetramerization domain and alters the ability of p53 to form stablizing oligomers with high DNA-binding capacity in cells with elevated pH levels. This pH dependence may explain the incomplete penetrance observed in many families carrying the p.R337H mutation and has led to the hypothesis that p.R337H is a conditional mutant (DiGiammarino et al. Nat Struct Biol. 2002, 9:12-6; Giacomazzi J, et al. BMC Cancer 2013 Apr;13(1):187). Given the inter-familial variability in penetrance and tumor patterns described to date, some have suggested that surveillance recommendations for p.R337H carriers should be based on family cancer history (Palmero et al. Cancer Lett. 2008 Mar 8;261(1):21-5). Based on the available evidence, p.R337H is classified as a pathogenic mutation.
Invitae RCV000197240 SCV000253848 pathogenic Li-Fraumeni syndrome 2020-10-30 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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413754 SCV000492466 pathogenic Breast neoplasm criteria provided, single submitter research
Color Health, Inc RCV000128923 SCV000537678 pathogenic Hereditary cancer-predisposing syndrome 2020-10-19 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the variant protein impacted protein stability and tetramerization, however, this defect may appear mild in some transactivation and growth inhibition assays (PMID: 9582268, 12826609, 20407015, 30224644; and IARC database). This variant is known to be a Brazilian founder mutation and observed in approximately 0.3% of the population in southern Brazil (PMID: 24936644, 27663983). This variant has been reported in numerous Brazilian individuals and families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 10864200, 16033918, 21192060, 27714481), Li-Fraumeni-like syndrome (PMID: 16494995), and early-onset breast cancer (PMID: 19046423, 22455664, 27223487). Studies of families carrying this variant have shown extremely variable cancer risk in individuals and identified several unaffected adult carriers, suggesting age-dependent (and possibly incomplete) penetrance of this variant (PMID: 19717094). This variant has been identified in 3/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg337Cys, p.Arg337Leu and p.Arg337Pro) have been reported as disease-causing in ClinVar (variation ID: 142536, 142828, 177879), suggesting that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic.
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.
Counsyl RCV000576817 SCV000677744 pathogenic Li-Fraumeni syndrome 1 2017-02-16 criteria provided, single submitter clinical testing
Mendelics RCV000197240 SCV000839103 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000989700 SCV001140239 pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000481814 SCV001247042 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000197240 SCV001547487 likely pathogenic Li-Fraumeni syndrome 2020-03-06 criteria provided, single submitter clinical testing Data included in classification: Multiple case reports of this variant in the literature in cases meeting Chompret criteria, due to its identification in children with adrenocortical cancer. 117 reports on IARC database (germline). (PS4_Strong). Variant is absent from 56,697 NFE gnomAD controls (N.B. present in 2 latino controls and 1 other but known to be a founder mutation in the Brazilian population) (PM2_sup). Variant predicted as deleterious by BayesDel 0.178 and AlignGVGD C25 (PP3_sup) Data not included in classification: 2* classification of pathogenic on ClinVar, multiple submitters Kato et al, 2003: variant is partially functional on yeast based assay (PMID: 12826609). Giacomelli et al 2008 (PMID: 30224644) no dominant negative activity or loss of function shown on functional studies.
OMIM RCV000013178 SCV000033425 pathogenic Adrenocortical carcinoma, pediatric 2006-01-01 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000481814 SCV000692060 pathogenic not provided no assertion criteria provided clinical testing
Nilou-Genome Lab RCV001375632 SCV001572529 pathogenic Adrenocortical carcinoma, hereditary 2021-04-27 no assertion criteria provided clinical testing A 4-year-old girl with metastatic adrenocortical carcinoma in the right kidney & multiple gallstones. The father also has this type of cancer.

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