ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1099G>A (p.Val367Ile) (rs746889239)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226146 SCV000285044 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 367 of the PMS2 protein (p.Val367Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs746889239, ExAC 0.03%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 237879). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000481764 SCV000572664 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1099G>A at the cDNA level, p.Val367Ile (V367I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val367Ile was observed at an allele frequency of 0.03% (5/16510) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Val367Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Val367Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569779 SCV000663513 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-25 criteria provided, single submitter clinical testing Insufficient evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481764 SCV000889604 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing
Color RCV000569779 SCV000911235 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001162267 SCV001324214 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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