Submissions for variant NM_000535.7(PMS2):c.1703C>G (p.Pro568Arg)

dbSNP: rs869312801

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210189	SCV000266217	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000217199	SCV000276656	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.P568R variant (also known as c.1703C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1703. The proline at codon 568 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in an individual with primary peritoneal cancer and family history of breast cancer, pancreatic cancer, and lymphoma (Shirts BH et al. Genet. Med. 2016 10;18:974-81).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524444	SCV000552026	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 568 of the PMS2 protein (p.Pro568Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with primary peritoneal cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224585). 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 PMS2 protein function with a negative predictive value of 80%. 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	RCV000479827	SCV000568115	uncertain significance	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with peritoneal cancer (Shirts et al., 2016); This variant is associated with the following publications: (PMID: 26845104)
Color Diagnostics, LLC DBA Color Health	RCV000217199	SCV000903281	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 568 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with peritoneal cancer with a family history of pancreatic cancer, breast cancer, and lymphoma (PMID: 26845104). This variant has been identified in 1/251372 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479827	SCV002046563	uncertain significance	not provided	2021-01-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468975	SCV004205374	uncertain significance	Lynch syndrome 4	2023-10-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493511	SCV004243280	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000210189	SCV004844150	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 568 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with peritoneal cancer with a family history of pancreatic, breast and lymphoma cancer (PMID: 26845104). This variant has been identified in 1/251372 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.