ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1714G>A (p.Ala572Thr) (rs63751023)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165566 SCV000216300 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Insufficient evidence
GeneDx RCV000513405 SCV000565789 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1714G>A at the cDNA level, p.Ala572Thr (A572T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant was observed in a cohort that underwent clinical genetic testing for Lynch syndrome (Yurgelun 2015). 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 Ala572Thr 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 information, it is unclear whether PMS2 Ala572Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513405 SCV000609249 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Counsyl RCV000662642 SCV000785329 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-06 criteria provided, single submitter clinical testing
Color RCV000165566 SCV000910898 likely benign Hereditary cancer-predisposing syndrome 2015-12-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193214 SCV001361921 uncertain significance not specified 2019-08-23 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1714G>A (p.Ala572Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251334 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (8e-05 vs 0.00011), allowing no conclusion about variant significance. The variant, c.1714G>A, has been reported in the literature in individuals affected with Lynch syndrome-associated cancer and/or polyp (Yurgelun_2015). The report does 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. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as Likely benign (1x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.