ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.682G>A (p.Gly228Ser) (rs376258383)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212847 SCV000149609 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.682G>A at the cDNA level, p.Gly228Ser (G228S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Gly228Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Gly228Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115700 SCV000217475 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-08 criteria provided, single submitter clinical testing ​<span style="background-color:initial">The p.G228S<span style="background-color:initial"> variant (also known as c.682G>A), located in coding exon 6 of the PMS2 <span style="background-color:initial">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 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 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 228 of the PMS2 protein (p.Gly228Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs376258383, ExAC 0.02%). This variant has been observed in individual(s) with colon cancer (PMID: 31433215). ClinVar contains an entry for this variant (Variation ID: 127794). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 Hereditary nonpolyposis colorectal cancer type 4 2018-04-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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 2020-02-05 criteria provided, single submitter clinical testing
Color Health, Inc 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.

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