Submissions for variant NM_000546.6(TP53):c.328C>T (p.Arg110Cys)

gnomAD frequency: 0.00001  dbSNP: rs587781371

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131196	SCV000186146	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-09	criteria provided, single submitter	clinical testing	The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in both cases and controls in breast cancer case control studies, and has also been reported in a high-risk breast cancer proband from Sweden (Momozowa Y et al. Nat Commun 2018 10;9(1):4083; Dorling et al. N Engl J Med 2021 02;384:428-439; Kharaziha P et al. Clin Genet 2019 09;96(3):216-225). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni syndrome (LFS) based on personal and family history (Rines RD et al. Carcinogenesis. 1998 Jun;19(6):979-84; Masciari S et al. Genet Med. 2011 Jul;13(7):651-7). This alteration has been observed in individuals with TP53 related tumors, but not classic Li-Fraumeni syndrome (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195648	SCV000254629	uncertain significance	Li-Fraumeni syndrome	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein (p.Arg110Cys). This variant is present in population databases (rs587781371, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 31081129, 32885271; internal data). ClinVar contains an entry for this variant (Variation ID: 142206). Invitae Evidence Modeling incorporating data from in vitro 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9290701, 12826609, 29979965, 30224644, 31081129). 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.
GeneDx	RCV001704056	SCV000491052	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 34605602, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 31081129, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609, 11782540, 25952993, 23246812, 22186996, 21519010, 21343334, 20407015, 17606709, 27276561, 29979965, 37352403, 30224644, 36353970, 32885271, 15510160, 30327374, 30613367, 27463065, 27895058, 27959731, 27680515, 26230955)
Color Diagnostics, LLC DBA Color Health	RCV000131196	SCV000686732	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267879	SCV002551091	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000131196	SCV002582115	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288646	SCV002582676	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149906	SCV003838581	uncertain significance	Breast and/or ovarian cancer	2021-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267879	SCV004100274	uncertain significance	not specified	2023-09-29	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. 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 2e-05 in 251288 control chromosomes. c.328C>T has been reported in the literature in individuals affected with various cancers without evidence of causality (e.g. Kharaziha_2019, Kobayashi_2018, LernerEllis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Kharaziha_2019). The following publications have been ascertained in the context of this evaluation (PMID: 9290701, 31081129, 30613367, 32885271). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
All of Us Research Program, National Institutes of Health	RCV000195648	SCV004823815	uncertain significance	Li-Fraumeni syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001704056	SCV005625955	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	The TP53 c.328C>T (p.Arg110Cys) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (PMIDs: 31081129 (2019), 32885271 (2021), and 33471991 (2021)). Functional studies demonstrated that the effect on protein function was inconclusive (PMIDs: 9290701 (1997), 12826609 (2003), 29979965 (2018) and 31081129 (2019)). The frequency of this variant in the general population, 0.00023 (5/21646 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356391	SCV001551544	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant (see examples: Holstege 2009, Pain 2017, Holstege 2010). The variant was also identified in dbSNP (ID: rs587781371) as “With Uncertain significance allele”, in ClinVar (classified as a variant of uncertain significance 4x by Ambry Genetics, Color Genomics, Invitae, and GeneDx), Cosmic (17x somatic entries), and IARC TP53 Database (13 somatic mutations). The variant was not identified in COGR, LOVD 3.0, or the Database of germline p53 mutations. The variant was identified in control databases in 5 of 246096 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the Finnish population in 5 of 22298 chromosomes (freq: 0.000224), but not in the African, Ashkenazi Jewish, East Asian, European (Non-Finnish), Latino, or South Asian populations. The p.Arg110 residue has been classified as a somatic mutational hotspot (Walker et al 1999). Variants at the same amino acid residue have been previously seen and are classified on ClinVar: p.Arg110Pro is classified as likely pathogenic; p.Arg110Leu is classified as likely pathogenic and as a variant of uncertain significance; and p.Arg110Ser and p.Arg110His are both classified as variants of uncertain significance. The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
BRCAlab, Lund University	RCV000131196	SCV002589019	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004797599	SCV005419172	uncertain significance	TP53-related disorder	2024-10-01	no assertion criteria provided	clinical testing