ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.497T>C (p.Leu166Pro) (rs116349687)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080227 SCV000166388 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129051 SCV000183746 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000587642 SCV000211590 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.497T>C at the cDNA level, p.Leu166Pro (L166P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). This variant has been reported in individuals with endometrial cancer, colorectal cancer, or prostate cancer, with a colon tumor from at least one individual showing loss of MLH1 and PMS2 proteins on immunohistochemistry (Ring 2016, Yurgelun 2017, Beebe-Dimmer 2018). PMS2 Leu166Pro was observed at an allele frequency of 0.27% (65/23,940) in individuals of African ancestry 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 a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Leu166Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587642 SCV000601851 likely benign not provided 2019-04-15 criteria provided, single submitter clinical testing
Color RCV000129051 SCV000686212 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587642 SCV000697370 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.497T>C (p.Leu166Pro) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the histidine kinase-like ATPase, C-terminal domain (InterPro) and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC (25/119118 control chromosomes), predominantly observed in the African subpopulation at a frequency of 0.002525 (24/9506). This frequency is about 22 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this may be a benign polymorphism found primarily in the populations of African origin. However, due to high sequence homology pseudogenes related to PMS2, the frequencies reported in ExAC may be unreliable. In the literature, the variant has been detected in two unrelated individuals diagnosed with Lynch syndrome-related cancers (Ring et al, 2016; Yurgelun et al, 2015), but lack of cosegregation and co-occurrence data prevents the inference of a genotype-phenotype correlation. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations (likely benign and uncertain significance). Taken together, this variant is classified as VUS-possibly benign.
Mendelics RCV000708997 SCV000838194 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587642 SCV000860664 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing

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