Submissions for variant NM_000535.7(PMS2):c.766G>A (p.Gly256Ser)

gnomAD frequency: 0.00002  dbSNP: rs587782633

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132021	SCV000187080	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.G256S variant (also known as c.766G>A), located in coding exon 7 of the PMS2 gene, results from a G to A substitution at nucleotide position 766. The glycine at codon 256 is replaced by serine, an amino acid with similar properties. 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	RCV000167945	SCV000218593	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	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 256 of the PMS2 protein (p.Gly256Ser). This variant is present in population databases (rs587782633, gnomAD 0.003%). 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: 142671). 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.
GeneDx	RCV000588881	SCV000565833	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484, 27997549)
Color Diagnostics, LLC DBA Color Health	RCV000132021	SCV000686237	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 256 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 6/282076 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588881	SCV000697385	uncertain significance	not provided	2016-11-10	criteria provided, single submitter	clinical testing	Variant summary: The c.766G>A (p.Gly256Ser) in PMS2 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located within a region that has a high homology to C-terminal domain of DNA mismatch repair proteins. The functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a low frequency 0.000025 (3/120532 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0001) in this gene. The variant has not been reported in the affected individuals via published reports, but it was cited as VUS by reputable databases/clinical laboratories. At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
Counsyl	RCV000663252	SCV000786477	uncertain significance	Lynch syndrome 4	2018-05-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765961	SCV000897382	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588881	SCV001134614	uncertain significance	not provided	2023-07-15	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in control individuals in a large-scale breast cancer association study and as somatic variant in a neuroblastoma tumor (PMIDs: 33471991 (2021), 27997549 (2016)). The frequency of this variant in the general population, 0.000023 (3/128856 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000132021	SCV002530384	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663252	SCV004019787	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	RCV000663252	SCV004205408	uncertain significance	Lynch syndrome 4	2023-10-06	criteria provided, single submitter	clinical testing