Submissions for variant NM_000535.7(PMS2):c.1309C>T (p.Pro437Ser) (rs200726484)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164990	SCV000215684	likely benign	Hereditary cancer-predisposing syndrome	2018-12-29	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Co-occurence with mutation in same gene (phase unknown)
GeneDx	RCV000429937	SCV000516135	likely benign	not specified	2018-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000461904	SCV000551950	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 437 of the PMS2 protein (p.Pro437Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (rs200726484, ExAC no frequency). This variant has been observed in an individual affected with colon cancer in the Leiden Open-source Variation Database (PMID: 21520333). However, in that individual, a pathogenic allele was also identified in PMS2, which suggests that this c.1309C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 185547). An in vitro experimental study has shown that this missense change does not affect the DNA mismatch repair activity of the PMS2 protein (PMID: 27435373). 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	RCV000164990	SCV000691007	likely benign	Hereditary cancer-predisposing syndrome	2017-08-18	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000586893	SCV000697292	uncertain significance	not provided	2016-12-22	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.1309C>T (p.Pro437Ser) variant causes a missense change involving a non-conserved nucleotide, which 4/5 in silico tools predict a benign. A functional study indicates that the variant of interest acted comparable to wild type MMR function. In addition, the variant of interest was reported to co-occur with another pathogenic PMS2 variant, c.1079_1080del, in an individual diagnosed with CrC at 43 y/o. LOVD - InSiGHT cites the variant in a male (adenocarc conlon transversum); AMS criteria negative; TUMOR_IHC: MLH1: positive; MSH2: positive; MSH6: positive; PMS2: negative; MLH1 Methylation: no methylation; Method: MS-MLPA; Indicates that the patient carried another pathogenic PMS2 variant c.1079_1080del (Classified as Class 5 by InSiGHT). Therefore, the patient described in LOVD is likely to be the same patient reported in the published reference. Furthermore, the IHC pattern supports the notion that the co-occuring PMS2 variant was the likely cause of colorectal cancer in this patient. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP). A clinical diagnostic laboratory cites the variant as "likely benign." Therefore, due to the reported co-occurrence, and comparable wild type MMR properties, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."