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

gnomAD frequency: 0.00002  dbSNP: rs567102013

Total submissions: 12

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 (https://www.ncbi.nlm.nih.gov/clinvar/variation/186188/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.