ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs121912664
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Total submissions: 24
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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 2022-01-24 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 http://www-p53.iarc.fr/; 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 stabilizing 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 2024-01-19 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 337 of the TP53 protein (p.Arg337His). This variant is present in population databases (rs121912664, gnomAD 0.006%). This missense change has been observed in individual(s) with multiple types of cancer (PMID: 10864200, 16033918, 16494995, 21192060, 23733769). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12379). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 9704930, 12826609, 20407015). This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9704931, 20407015). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Diagnostics, LLC DBA Color Health RCV000128923 SCV000537678 pathogenic Hereditary cancer-predisposing syndrome 2023-05-16 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 2022-09-29 criteria provided, single submitter clinical testing Founder variant present in 0.2-0.3% of the South Brazilian population (Garritano et al., 2010); Reported to result in lower cancer risks by early adulthood than variants associated with classic Li-Fraumeni syndrome, with a 21% risk of cancer reported by age 45 per one study, but comparable lifetime cancer risks (Garritano et al., 2010; Mastellaro et al., 2017); Published functional studies demonstrate a damaging effect: reduced ability to form tetramers resulting in reduced transactivation in a pH-dependent manner, increased tumorigenesis in a knock-in mouse model (DiGiammarino et al., 2002; Jordan et al., 2010; Park 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: 19717094, 10864200, 15121773, 23794094, 11753428, 28369373, 27866339, 30588330, 29039119, 30535581, 32592449, 31978118, 21343334, 11481490, 12826609, 21192060, 18248785, 22170717, 22455664, 16033918, 23259501, 23733769, 21445348, 9704930, 11600572, 25736369, 21468523, 19046423, 22004116, 23570263, 16750598, 24784157, 23056559, 24936644, 26452166, 19877175, 27223487, 27275664, 26656232, 27663983, 28387921, 27081505, 25945745, 26823150, 28114597, 28254861, 16494995, 28968711, 28152038, 28864397, 28724667, 28472496, 30774760, 27714481, 30596752, 29392648, 29928384, 30042151, 30107858, 31748977, 29625052, 32039725, 32671623, 33603772, 30224644, 32485079, 31744167, 31889631, 33138793, 31778928, 26681051, 31105275, 31494577, 20407015, 15510160, 33258288, 33637564, 32986223, 32817165, 29922827, 30982232, 32156018)
Counsyl RCV000576817 SCV000677744 pathogenic Li-Fraumeni syndrome 1 2017-02-16 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
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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000481814 SCV001762195 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000576817 SCV002030174 pathogenic Li-Fraumeni syndrome 1 2021-02-09 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
DASA RCV000576817 SCV002097308 pathogenic Li-Fraumeni syndrome 1 2022-02-14 criteria provided, single submitter clinical testing Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28369373; 20407015) - PS3. The c.1010G>A;p.(Arg337His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12379; PMID: 20301488; 28387921; 28864397; 28984303; 28968711; 28756477; 30107858) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (P53_tetramer) - PM1. Pathogenic missense variant in this residue have been reported (ClinVar ID: 142536 - c.1009C>T;p.(Arg337Cys)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
Genetics Program, Instituto Nacional de Cancer RCV002307364 SCV002515183 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-01 criteria provided, single submitter research
Genome-Nilou Lab RCV000128923 SCV002582334 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000576817 SCV002582996 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496338 SCV002811422 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5 2022-03-25 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000576817 SCV004183390 pathogenic Li-Fraumeni syndrome 1 2021-10-14 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PS4, PP1
Baylor Genetics RCV001375632 SCV004206232 pathogenic Adrenocortical carcinoma, hereditary 2023-12-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481814 SCV004221343 pathogenic not provided 2022-10-07 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000012 (3/250846 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a Brazilian founder mutation associated with reduced penetrance, carrying a lower cancer risk than other TP53 pathogenic variants (PMID: 33300245 (2021), 31744167 (2019), 19877175 (2009)). It has been reported in up to 0.2 to 0.3% of the Brazilian population (PMID: 32592449 (2049), 19717094 (2009)). This variant has been seen in individuals with breast cancer (PMID: 32986223 (2021), 32039725 (2020), 30596752 (2018), 22455664 (2012)), Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 30107858 (2018), 29392648 (2018), 28756477 (2018), 21192060 (2011)), and children with adrenocortical tumors (ACT) (PMID: 32156018 (2020), 31744167 (2019), 16033918 (2006), 16033918 (2006), 15121773 (2004), 11481490 (2001)). Some published functional studies are conflicting, but the majority have found that this variant causes a partial or conditional damaging effect on TP53 function (PMID: 35367578 (2022), 33637564 (2021), 30042151 (2018), 28369373 (2017), 23056559 (2012), 21343334 (2011), 20407015 (2010), 12826609 (2003), 11753428 (2002), 9704930 (1998)). Based on the available information, this variant is classified as a pathogenic variant with reduced penetrance.
All of Us Research Program, National Institutes of Health RCV000197240 SCV004823731 pathogenic Li-Fraumeni syndrome 2023-12-18 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000197240 SCV004847779 pathogenic Li-Fraumeni syndrome 2019-10-17 criteria provided, single submitter clinical testing The p.Arg337His variant in TP53 has been reported in numerous individuals with Li-Fraumeni syndrome and is thought to be a founder allele in Southern Brazil (Achatz 2016, Andrade 2016, Borges 2016). Although cancers associated with this allele tend to occur at a later age compared to other pathogenic variants in TP53, the lifetime risk seems to be similar to other LFS-associated TP53 variants (Garritano 2010). This variant has also been reported in ClinVar (Variation ID 12379). It has been identified in 0.007% (2/24544) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additional variants involving this codon (p.Arg337Cys, p.Arg337Leu) have been identified in individuals with cancer and are classified as likely pathogenic/pathogenic by clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PS4, PP1_strong, PP3, PM5.
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
Genome-Nilou 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.
Laboratory for Genotyping Development, RIKEN RCV003162248 SCV002758162 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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