Submissions for variant NM_000535.7(PMS2):c.682G>A (p.Gly228Ser)

gnomAD frequency: 0.00005  dbSNP: rs376258383

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212847	SCV000149609	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27882345, 32980694, 11574484, 31433215, 33471991, 31391288)
Ambry Genetics	RCV000115700	SCV000217475	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The p.G228S variant (also known as c.682G>A), located in coding exon 6 of the PMS2 gene, results from a G to A substitution at nucleotide position 682. The glycine at codon 228 is replaced by serine, an amino acid with similar properties. This alteration was detected in a cohort of 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (Djursby M et al. Front Genet, 2020 Sep;11:566266). This amino acid position is highly 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.
Invitae	RCV000472958	SCV000551937	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 228 of the PMS2 protein (p.Gly228Ser). This variant is present in population databases (rs376258383, gnomAD 0.01%). This missense change has been observed in individual(s) with colon cancer (PMID: 31433215). ClinVar contains an entry for this variant (Variation ID: 127794). 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.
Counsyl	RCV000663188	SCV000786360	uncertain significance	Lynch syndrome 4	2018-04-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212847	SCV000806220	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212847	SCV000889637	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000035 (4/113762 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 31433215 (2019)). Additionally, the variant was found both in individuals with breast cancer as well as unaffected individuals in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000115700	SCV000902891	benign	Hereditary cancer-predisposing syndrome	2016-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193815	SCV001362949	uncertain significance	not specified	2019-03-28	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.682G>A (p.Gly228Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 246262 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.682G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000115700	SCV002530378	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193815	SCV002550748	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663188	SCV004019795	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.
Baylor Genetics	RCV000663188	SCV004205378	uncertain significance	Lynch syndrome 4	2023-10-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492488	SCV004239601	uncertain significance	Breast and/or ovarian cancer	2022-08-12	criteria provided, single submitter	clinical testing