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

dbSNP: rs587782529

Total submissions: 13

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475086	SCV000545330	pathogenic	Li-Fraumeni syndrome	2024-08-01	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	Ovarian neoplasm	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.