ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.936G>A (p.Met312Ile) (rs139194813)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132451 SCV000187545 likely benign Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Color RCV000132451 SCV000902808 likely benign Hereditary cancer-predisposing syndrome 2016-03-15 criteria provided, single submitter clinical testing
Counsyl RCV000662505 SCV000785032 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-03-17 criteria provided, single submitter clinical testing
GeneDx RCV000590247 SCV000211578 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.936G>A at the cDNA level, p.Met312Ile (M312I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Met312Ile was observed at an allele frequency of 0.1065% (11/10,324) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Met312Ile occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Met312Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590247 SCV000697403 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.936G>A (p.Met312Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 11/120600 control chromosomes at a frequency of 0.0000912, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). This variant has been reported in at least two affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000167877 SCV000218523 benign Hereditary nonpolyposis colon cancer 2018-01-04 criteria provided, single submitter clinical testing

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