Submissions for variant NM_000546.6(TP53):c.587G>A (p.Arg196Gln)

gnomAD frequency: 0.00001  dbSNP: rs483352697

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196467	SCV000254632	uncertain significance	Li-Fraumeni syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 196 of the TP53 protein (p.Arg196Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with aplastic anemia and/or breast cancer (PMID: 27418648, 30607672; Invitae). ClinVar contains an entry for this variant (Variation ID: 216467). 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: 12826609, 29979965). 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	RCV000235733	SCV000292696	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: some found partially functional transactivation in yeast-based assays, while other studies do not support a dominant-negative effect (Marutani et al., 1999; Monti et al., 2003; Kato et al., 2003; Kotler et al., 2018; Giacomelli et al., 2018); Observed in the germline of a patient with aplastic anemia, as well as individuals with breast cancer (Keel et al., 2016; Momozawa et al., 2018; Bakhuizen et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 10519380, 12917626, 8156519, 11007040, 26319365, 26314856, 21197471, 28476805, 24665023, 27418648, 29979965, 30224644, 30287823, 33240649, 30607672, 30840781, 15510160, 33471991, 12826609)
Color Diagnostics, LLC DBA Color Health	RCV000580263	SCV000686754	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 12917626) and functional in human cell proliferation assay (PMID: 29979965). This variant has been reported in two individuals affected with breast cancer (PMID: 30287823, 30607672, 33471991), including a proband with early-onset breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 30607672). This variant has been identified in 1/251484 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.
Ambry Genetics	RCV000580263	SCV001186682	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The p.R196Q variant (also known as c.587G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 587. The arginine at codon 196 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in a 6-year-old male with aplastic anemia and has also been reported in multiple breast cancer cases (Keel SB et al. Haematologica 2016 11;101(11):1343-1350; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Bakhuizen JJ et al. Fam Cancer, 2019 04;18:273-280; Dorling et al. N Engl J Med, 2021 02;384:428-439). This variant is in the functionally critical DNA binding domain of the TP53 protein, is reported to have partial loss of transactivation capacity, and is predicted to affect all p53 isoforms (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8; 100(14):8424-9). One yeast-based functional assay did not show this alteration to have a dominant negative effect (Marutani M et al. Cancer Res. 1999 Oct;59(19):4765-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Eldar A et al. Nucleic Acids Res, 2013 Oct;41:8748-59). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229122	SCV002511555	uncertain significance	not specified	2022-04-16	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.587G>A (p.Arg196Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.587G>A has been reported in the literature as a presumed germline variant in an individual with early-onset breast cancer (example, Bakhuizen_2019), and in an individual with aplastic anemia (example, Keel_2016) and also reported in multiple cancers (COSMIC database). 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 (Kato_2003). The most pronounced variant effect results in 66% of normal activity being characterized as partially-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000580263	SCV002582051	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288817	SCV002582369	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235733	SCV004221366	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 8156519 (1994), 30287823 (2018), and 33471991 (2021)), as well as in an individual with early-onset breast cancer that met the Chompret criteria for Li-Fraumeni syndrome (PMID: 30607672 (2019)). Functional studies using human cell lines and yeast based assays demonstrated that this variant does not significantly impact protein function (PMIDs: 10519380 (1999), 12917626 (2003), 29979965 (2016), and 30224644 (2018)). The frequency of this variant in the general population, 0.000004 (1/251484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000196467	SCV004823781	uncertain significance	Li-Fraumeni syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 12917626) and functional in human cell proliferation assay (PMID: 29979965). This variant has been reported in two individuals affected with breast cancer (PMID: 30287823, 30607672, 33471991), including a proband with early-onset breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 30607672). This variant has been identified in 1/251484 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.
Baylor Genetics	RCV004567435	SCV005054339	uncertain significance	Adrenocortical carcinoma, hereditary	2024-02-06	criteria provided, single submitter	clinical testing