Submissions for variant NM_000535.7(PMS2):c.1624A>C (p.Thr542Pro)

gnomAD frequency: 0.00001  dbSNP: rs1425816147

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001768213	SCV002008668	uncertain significance	not provided	2019-12-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002405310	SCV002708058	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	The p.T542P variant (also known as c.1624A>C), located in coding exon 11 of the PMS2 gene, results from an A to C substitution at nucleotide position 1624. The threonine at codon 542 is replaced by proline, an amino acid with highly similar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This amino acid position is poorly 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	RCV002540683	SCV003469297	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 542 of the PMS2 protein (p.Thr542Pro). This variant is present in population databases (no rsID available, gnomAD 0.03%). 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: 1318589). 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003154042	SCV003843537	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004009037	SCV004833446	uncertain significance	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with proline at codon 542 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 not been reported in an individual affected with heriditary breast or ovarian cancer (PMID: 31742824). This variant has been identified in 5/282208 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.