ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.964G>A (p.Val322Ile) (rs587782208)

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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 RCV000130884 SCV000185792 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212861 SCV000211599 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.964G>A at the cDNA level, p.Val322Ile (V322I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val322Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Val322Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species 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 evidence, it is unclear whether PMS2 Val322Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411983 SCV000488569 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-04-28 criteria provided, single submitter clinical testing
Invitae RCV000467383 SCV000551982 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 322 of the PMS2 protein (p.Val322Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587782208, ExAC 0.002%). This variant has been reported in the literature an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 142066). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000130884 SCV000909663 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781751 SCV000920041 uncertain significance not specified 2017-09-18 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.964G>A (p.Val322Ile) variant located in the Ribosomal protein S5 domain 2-type fold (via InterPro) involves the alteration of a conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 2/246084 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, the technology utilized for this dataset do not rule out pseudogene interference and thus this data needs to be cautiously considered. A publication, Tung_2015, reports the variant to have been found in one BrC pt, however, limited information is provided (ie, lack of cosegregation data). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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