ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.755G>A (p.Cys252Tyr) (rs775445157)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000556803 SCV000625687 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 252 of the PMS2 protein (p.Cys252Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs775445157, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual with Lynch syndrome-associated cancers (Invitae). However, in that individual a pathogenic allele was also identified in MSH2, which suggests that this c.755G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 455741). 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: "Deleterious"; PolyPhen-2: "Probably 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.
Ambry Genetics RCV000564413 SCV000664900 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000564413 SCV000686235 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781740 SCV000920028 uncertain significance not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: PMS2 c.755G>A (p.Cys252Tyr) results in a non-conservative amino acid change located in the C-terminal domain of PMS2 (IPR013507) that functions in promoting dimerization (InterPro). Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.58 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin, however the technology utilized for this dataset does not rule out pseudogene interference and thus this data cannot be relied upon. To our knowledge, no occurrence of c.755G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with another likely pathogenic PMS2 variant have been found in two internal samples (PMS2 c.1908delA, p.Gln637fsX28), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, this variant is classified as VUS-possibly benign, until additional information becomes available.

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