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

gnomAD frequency: 0.00001  dbSNP: rs121912664

Total submissions: 27

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197240	SCV000253848	pathogenic	Li-Fraumeni syndrome	2024-12-05	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). Invitae Evidence Modeling incorporating data from in vitro 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.
Institute of Immunology and Genetics Kaiserslautern	RCV000576817	SCV005382098	pathogenic	Li-Fraumeni syndrome 1	2022-04-21	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000128923	SCV005407752	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	c.1010G>A, located in exon 10 of the TP53 gene, is predicted to result in the substitution of Arginine by Histidine at codon 337, p.(Arg337His). This variant is found in 1/236428 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. This variant has a BayesDel score 0.17 and Align GVGD (Zebrafish) is Class C0. Transactivation assays show a partially function allele according to Kato 2003 (PMID: 12826609) and there is a second assay showing low function (tetramer assay, PMID: 18940924) (PS3_Moderate). At least, this variant has been reported in 33 Chompret individuals, which awards 16 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 10864200, 16933305, 18270399, 21630152, 21440489, 22619358, 28453760, 30147334, among others) (PS4). It has been observed cosegregation (7 meiosis) in three families (PMID: 11521785, 27101110, 29956451) (PP1_Strong). In addition, this variant has been identified de novo in 4 individuals (PMID: 27601191, 27101110, 32292755) (PM6_Very Strong). The variant is present in >3 living unaffected individuals above 55 years of age (PMID: 17940213, 18373486) (BS4). This variant is a founder in Brasil. It has been reported in ClinVar (15x as pathogenic, 1x as likely pathogenic), LOVD (2x as pathogenic, 2x NA), CancerHotspots (4 somatic observations). Based on the currently available information, c.1010G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
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
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004797591	SCV005419170	pathogenic	TP53-related disorder	2024-10-01	no assertion criteria provided	clinical testing