ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2559C>G (p.Ile853Met) (rs371673459)

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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 RCV000132047 SCV000187109 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000199501 SCV000255295 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 853 of the PMS2 protein (p.Ile853Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 142688). This variant has been reported to have conflicting or insufficient data to determine the effect on PMS2 protein function (PMID: 28494185). 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 RCV000656953 SCV000565424 uncertain significance not provided 2018-11-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2559C>G at the cDNA level, p.Ile853Met (I853M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATC>ATG). This variant was classified as functional by several in vitro functional studies evaluating RNA and protein expression, viability, apoptosis induction, and DNA damage signaling (Arora 2017). This variant was observed in at least one individual with breast cancer, and in an individual with prostate and pancreatic cancer (Tung 2015, Dudley 2018). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in the endonuclease domain (Fukui 2011). 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 Ile853Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000479601 SCV000712799 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing The p.Ile853Met variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 7/25524 of South Asian chromosom es by the Genome Aggregation DAtabase (gnomAD http://gnomad.broadinstitute.org; dbSNP rs371673459). Computational prediction tools and conservation analysis sug gest that the p.Ile853Met variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, the clinic al significance of the p.Ile853Met variant is uncertain.
PreventionGenetics,PreventionGenetics RCV000656953 SCV000806156 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000479601 SCV000918048 uncertain significance not specified 2017-09-15 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2559C>G (p.Ile853Met) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 24/214886 control chromosomes at a frequency of 0.0001117, which is approximately equivalent to the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, a known PMS2 pseudogene complicates the interpretation of this control population data. The variant has been identified in a pancreatic cancer patient that also carried a CDNK2A mutation (mutation not specified) and a CFTR variant (p.A120T; PoDV), suggesting the variant of interest is not playing a role in cancer development (Yang_2016). In addition, a recent study assessed the functional effects of the variant via in vitro expression assays and cell-based MMR assays, all of which showed no or mild effect on function (Arora_2017). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance without supporting evidence for independent review. Given the functional data and the co-occurrences in a patient, this variant is classified as VUS-possibly benign.

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