ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1080A>G (p.Ile360Met)

gnomAD frequency: 0.00002  dbSNP: rs567102013
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165734 SCV000216475 likely benign Hereditary cancer-predisposing syndrome 2022-03-31 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001083209 SCV000219060 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000656945 SCV000279137 likely benign not provided 2021-03-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22949387, 27443514, 25186627)
Counsyl RCV000411319 SCV000489021 uncertain significance Lynch syndrome 4 2016-08-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000217127 SCV000540069 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant has not been seen in affected patients. MaxMAF is 0.14% (too high for disorder). AA is not conserved - Met seen in 2 mammals and many non-mammals.
Color Diagnostics, LLC DBA Color Health RCV000165734 SCV000911057 likely benign Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217127 SCV000918037 likely benign not specified 2018-02-07 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1080A>G (p.Ile360Met) results in a conservative amino acid change located in the DNA mismatch repair protein, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Latino control individuals (41/34364) in the gnomAD database is approximately 10.56 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 Latino origin. While PMS2 is known to have highly homologous pseudogenes which may interfere with the technology used in large population datasets like gnomAD, a BLAT search of the surrounding region showed no similar regions of the genome, allowing the population data to be utilized as strong evidence for the benign nature of this variant. c.1080A>G has been reported in the literature in an individual affected with endometrial carcinoma, without strong evidence for causality (Ring_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classify the variant as a VUS while one has classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656945 SCV002046097 likely benign not provided 2022-11-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000656945 SCV002506058 likely benign not provided 2022-01-12 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000165734 SCV002529754 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-18 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000411319 SCV004019780 uncertain significance Lynch syndrome 4 2023-04-04 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences RCV003907523 SCV004724066 uncertain significance PMS2-related disorder 2024-02-28 criteria provided, single submitter clinical testing The PMS2 c.1080A>G variant is predicted to result in the amino acid substitution p.Ile360Met. This variant has been reported in one individual with endometrial cancer; however no segregation or functional evidence was provided (Ring et al. 2016. PubMed ID: 27443514, Supp Table 2). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD and is listed in ClinVar with conflicting interpretations including likely benign and uncertain significance ( At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.