ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1009C>T (p.Arg337Cys)

dbSNP: rs587782529
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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 RCV000131726 SCV000186766 pathogenic Hereditary cancer-predisposing syndrome 2022-05-12 criteria provided, single submitter clinical testing The p.R337C pathogenic mutation (also known as c.1009C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). In addition, this variant has been detected in several individuals at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant in the tetramerization domain is reported as non-functional in yeast based assays of transactivation (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). A study conducted in human cell lines indicates that this alteration is deficient at growth suppression but has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000475086 SCV000545330 pathogenic Li-Fraumeni syndrome 2024-01-08 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 337 of the TP53 protein (p.Arg337Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni like syndrome (PMID: 9150393, 9452042, 17606709, 18511570, 20478780). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142536). 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 affects TP53 function (PMID: 9150393, 9704930, 9704931, 12826609, 20128691, 21343334). 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: 9704930, 10864200, 12826609, 16033918, 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.
Color Diagnostics, LLC DBA Color Health RCV000131726 SCV001354213 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-19 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 337 in the tetramerization domain 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 that this variant causes a partial loss of transactivation function of TP53 protein in yeast (PMID: 9150393, 12826609, 14559903, 20407015, 21343334) and mammalian cells (PMID: 9766574, 10653977, 19454241, 20128691, 20505364). This variant has been reported in individuals diagnosed with classic or Chompret Li-Fraumeni syndrome (PMID 9150393, 9452042, 18511570, 20478780) and in an individual with early-onset breast cancer (PMID: 29752822) This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg337His, have been reported as disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310211 SCV001499817 likely pathogenic Li-Fraumeni syndrome 1 2020-04-02 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001781474 SCV002022394 pathogenic not provided 2019-10-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000131726 SCV002582336 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001310211 SCV002582997 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000475086 SCV003844983 pathogenic Li-Fraumeni syndrome 2023-02-03 criteria provided, single submitter clinical testing Variant summary: TP53 c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250834 control chromosomes (gnomAD). c.1009C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Renaux-Petel_2017, Fischer_2018, Frone_2021). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (e.g. Lomax_1997, Kato_2003, Imagawa_2009, Fischer_2018). These studies indicate that the variant results in a substantial decrease in transcriptional activity compared to the WT protein and a reduction in tumor suppression functions including increased colony formation, decreased growth arrest, and impaired apoptotic response. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003467184 SCV004206244 pathogenic Adrenocortical carcinoma, hereditary 2023-08-11 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001310211 SCV004932361 likely pathogenic Li-Fraumeni syndrome 1 2024-02-21 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9150393, 20478780]. This variant is expected to disrupt protein structure [PMID: 20978130]. Functional studies indicate this variant impacts protein function [PMID: 9704930, 10653977, 9704931, 20978130, 9766574, 19454241, 9150393].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785479 SCV000924051 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
BRCAlab, Lund University RCV000131726 SCV002589039 likely pathogenic Hereditary cancer-predisposing syndrome 2022-08-26 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001310211 SCV004228479 not provided Li-Fraumeni syndrome 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 02-19-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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