ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.849T>A (p.Ser283Arg)

dbSNP: rs1277038817
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553271 SCV000625701 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-14 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 283 of the PMS2 protein (p.Ser283Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 455744). 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 expected to disrupt PMS2 protein function. 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 RCV001755792 SCV002005979 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25980754)
Ambry Genetics RCV002448607 SCV002678519 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-17 criteria provided, single submitter clinical testing The p.S283R variant (also known as c.849T>A), located in coding exon 8 of the PMS2 gene, results from a T to A substitution at nucleotide position 849. The serine at codon 283 is replaced by arginine, an amino acid with dissimilar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is highly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001755792 SCV004565142 uncertain significance not provided 2023-05-26 criteria provided, single submitter clinical testing The PMS2 c.849T>A; p.Ser283Arg variant (rs1277038817) is reported in the literature in two individuals affected with breast cancer or suspected Lynch syndrome (Tung 2015, Yurgelun 2015). This variant is also reported in ClinVar (Variation ID: 455744) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.701). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754.

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