Submissions for variant NM_000535.7(PMS2):c.378C>G (p.His126Gln)

dbSNP: rs768488890

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411482	SCV000489436	uncertain significance	Lynch syndrome 4	2016-10-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021140	SCV001182719	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.H126Q variant (also known as c.378C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 378. The histidine at codon 126 is replaced by glutamine, an amino acid with highly similar properties. 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.
Invitae	RCV001320218	SCV001510995	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 126 of the PMS2 protein (p.His126Gln). This variant is not present in population databases (gnomAD no frequency). 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: 237914). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV001775698	SCV002012654	uncertain significance	not provided	2019-11-05	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV001021140	SCV002053056	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 126 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 not been identified 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.
Myriad Genetics, Inc.	RCV000411482	SCV004019858	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003998792	SCV004842117	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 126 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 not been identified 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.