ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1567T>A (p.Ser523Thr) (rs63751132)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656949 SCV000149570 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1567T>A at the cDNA level, p.Ser523Thr (S523T) at the protein level, and results in the change of a Serine to a Threonine (TCC>ACC). This variant has been reported in an individual with breast cancer and in at least two individuals with colorectal cancer (Shirts 2016, Tung 2016, Yurgelun 2017). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Ser523Thr is not located in a known functional domain. 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 Ser523Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115661 SCV000187249 likely benign Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Structural Evidence
Invitae RCV001082540 SCV000254601 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000197412 SCV000266216 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121851 SCV000601824 uncertain significance not specified 2016-09-19 criteria provided, single submitter clinical testing
Counsyl RCV000662627 SCV000785296 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-06-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656949 SCV000806144 uncertain significance not provided 2015-12-01 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115661 SCV000822123 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000115661 SCV000910645 likely benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121851 SCV000918047 uncertain significance not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1567T>A (p.Ser523Thr) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251178 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), however this data must be interpreted with caution as the sequencing techology utalized does not distinguish between PMS2 and highly homologous pseudogenes. c.1567T>A has been reported in the literature in individuals affected with Lynch Syndrome and other types of cancer (Nomura_2015, He_2016, Shirts_2016, Tung_2016, Yurgelun_2017, Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.1492del11; Nomura_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (7 VUS, 2 likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
ITMI RCV000121851 SCV000086052 not provided not specified 2013-09-19 no assertion provided reference population

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