Submissions for variant NM_000535.7(PMS2):c.1126C>T (p.Pro376Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881911

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160888	SCV000211580	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000217986	SCV000278577	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing	The p.P376S variant (also known as c.1126C>T), located in coding exon 10 of the PMS2 gene, results from a C to T substitution at nucleotide position 1126. The proline at codon 376 is replaced by serine, an amino acid with similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000217986	SCV000690998	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 376 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 PMS2-related disorders in the literature. This variant has been identified in 4/282686 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.
Invitae	RCV000694862	SCV000823324	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 376 of the PMS2 protein (p.Pro376Ser). This variant is present in population databases (rs730881911, gnomAD 0.005%). 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: 182803). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251394	SCV001426980	uncertain significance	not specified	2020-07-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1126C>T (p.Pro376Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251302 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1126C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998524	SCV004839846	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 376 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 PMS2-related disorders in the literature. This variant has been identified in 4/282686 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.