ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1080A>G (p.Ile360Met) (rs567102013)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165734 SCV000216475 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-08 criteria provided, single submitter clinical testing The p.I360M variant (also known as c.1080A>G), located in coding exon 10 of the PMS2 gene, results from an A to G substitution at nucleotide position 1080. The isoleucine at codon 360 is replaced by methionine, an amino acid with highly similar properties. <span style="background-color:initial">This alteration was detected in a cohort of 381 unselected patients with endometrial cancer (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001083209 SCV000219060 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000656945 SCV000279137 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1080A>G at the cDNA level, p.Ile360Met (I360M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant has been observed in at least one individual with endometrial cancer (Ring 2016). PMS2 Ile360Met was observed at an allele frequency of 0.12% (41/34,364) in individuals of Latino 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Ile360Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411319 SCV000489021 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-08-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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 Health, Inc 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.

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