ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.101G>T (p.Ser34Ile) (rs370612538)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166613 SCV000217417 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000231923 SCV000285040 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 34 of the PMS2 protein (p.Ser34Ile). The serine residue is weakly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs370612538, ExAC 0.01%). This variant has been observed in an individual affected with head and neck squamous cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 186945). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000485924 SCV000565380 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.101G>T at the cDNA level, p.Ser34Ile (S34I) at the protein level, and results in the change of a Serine to an Isoleucine (AGT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ser34Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Ser34Ile is located in the ATPase domain (Guarne 2001). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Ser34Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166613 SCV000686089 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780635 SCV000918066 uncertain significance not specified 2019-10-03 criteria provided, single submitter clinical testing Variant summary: PMS2 c.101G>T (p.Ser34Ile) results in a non-conservative amino acid change located in the ATPase domain (IPR003594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245786 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (4.1e-05 vs 0.00011), allowing no conclusion about variant significance. To our knowledge, c.101G>T has not been reported in the literature in individuals affected with Lynch Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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