ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1732C>T (p.Arg578Cys) (rs63750534)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000662641 SCV000785328 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-06 criteria provided, single submitter clinical testing
Invitae RCV000695037 SCV000823512 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 578 of the PMS2 protein (p.Arg578Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in two siblings affected with constitutional mismatch repair deficiency (CMMR-D) associated tumors, who also carried two additional pathogenic PMS2 variants (PMID: 17557300). In these individuals, the c.1732C>T variant was found to be in cis with an adjacent PMS2 truncating variant (c.1730dupA, also known as c.1730_1731insA). In these affected individuals, this variant was shown to be derived from the PMS2CL pseudogene by a gene conversion event (PMID: 17557300). ClinVar contains an entry for this variant (Variation ID: 91311). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine 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.
Color RCV001181986 SCV001347261 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing

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