ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.1135C>A (p.Arg379Ser)

dbSNP: rs749061599
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000412389 SCV001737920 likely benign Li-Fraumeni syndrome 1 2021-04-12 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, TP53 c.1135C>A (p.Arg379Ser) meets criteria to be classified as Likely Benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4, BS3_Supporting.
Ambry Genetics RCV000166408 SCV000217202 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-29 criteria provided, single submitter clinical testing The p.R379S variant (also known as c.1135C>A), located in coding exon 10 of the TP53 gene, results from a C to A substitution at nucleotide position 1135. The arginine at codon 379 is replaced by serine, an amino acid with dissimilar properties. This alteration was previously reported in an individual diagnosed with ovarian cancer at 54 years, who had a family history of breast and prostate cancer (Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102). This variant is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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 limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000236607 SCV000293283 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1135C>A at the cDNA level, p.Arg379Ser (R379S) at the protein level, and results in the change of an Arginine to a Serine (CGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg379Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg379Ser occurs at a position that is not conserved and is located within the C-terminal regulatory domain (Bode 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg379Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000412389 SCV000489454 uncertain significance Li-Fraumeni syndrome 1 2016-10-06 criteria provided, single submitter clinical testing
Invitae RCV000795303 SCV000934758 uncertain significance Li-Fraumeni syndrome 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 379 of the TP53 protein (p.Arg379Ser). This variant is present in population databases (rs749061599, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 186762). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 30224644). 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.
Color Diagnostics, LLC DBA Color Health RCV000166408 SCV001359321 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-21 criteria provided, single submitter clinical testing This missense variant replaces arginine with serine at codon 379 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 that this variant is functional in yeast based transactivation studies and human cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in an individual affected with ovarian cancer (PMID: 27616075). This variant has been identified in 1/251414 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.
CeGaT Center for Human Genetics Tuebingen RCV000236607 SCV001747795 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000412389 SCV004017853 uncertain significance Li-Fraumeni syndrome 1 2023-04-11 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.