Submissions for variant NM_000535.7(PMS2):c.847A>C (p.Ser283Arg)

gnomAD frequency: 0.00001  dbSNP: rs876660871

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220531	SCV000278649	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	The p.S283R variant (also known as c.847A>C), located in coding exon 8 of the PMS2 gene, results from an A to C substitution at nucleotide position 847. The serine at codon 283 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps. (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000767166	SCV000279719	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25186627, 11574484, 25980754)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767166	SCV000601862	uncertain significance	not provided	2019-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV000545236	SCV000625700	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	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 0.03%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 234135). 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 with a positive 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.
Color Diagnostics, LLC DBA Color Health	RCV000220531	SCV000686245	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 283 of the PMS2 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of Lynch Syndrome in the literature (PMID: 25980754). This variant has been identified in 3/282838 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.
Baylor Genetics	RCV003463600	SCV004205341	uncertain significance	Lynch syndrome 4	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998602	SCV004839901	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 283 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282838 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.