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 colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129051 SCV000183746 likely benign Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing Other data supporting benign classification;Other strong data supporting benign classification
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 2020-05-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129051 SCV000686212 likely benign Hereditary cancer-predisposing syndrome 2020-03-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175360 SCV000697370 likely benign not specified 2019-12-09 criteria provided, single submitter clinical testing Variant summary: PMS2 c.497T>C (p.Leu166Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) 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 0.00022 in 250284 control chromosomes, predominantly at a frequency of 0.0032 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.497T>C has been reported in the literature in sequencing studies of individuals affected with Lynch syndrome associated cancer/colorectal polyps, endometrial cancer, and early onset prostate cancer (example, Yurgelun_2017, Ring_2016, Yurgelun_2017, Beebe-Dimmer_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6, likely benign, n=1). Based on the evidence outlined above, and no emerging evidence supporting a pathognomic outcome for this variant in its evaluations spanning four years of testing at our laboratory, the variant was re-classified as likely 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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