Submissions for variant NM_000535.7(PMS2):c.319C>T (p.Arg107Trp)

gnomAD frequency: 0.00001  dbSNP: rs188006077

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586637	SCV000149602	likely pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27742654, 26110232, 25512458, 26247049, 27435373, 11574484, 30702970, 29445031, 31783044, 36690767, 32571878)
Ambry Genetics	RCV000115693	SCV000187425	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	The p.R107W variant (also known as c.319C>T), located in coding exon 4 of the PMS2 gene, results from a C to T substitution at nucleotide position 319. The arginine at codon 107 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in trans with a PMS2 exon 10 deletion in a patient with suspected CMMRD; however, PMS2 protein expression was normal by immunohistochemistry (IHC) performed on the patient's tumor sample (van der Klift HM et al. Hum. Mutat. 2016 Nov;37:1162-1179). This alteration has also been identified in several individuals whose family history met Amsterdam II criteria for Lynch syndrome and/or colorectal tumors showed normal PMS2 protein expression on IHC, but displayed high microsatellite instability (MSI-H) (Ambry internal data; van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). In an in vitro mismatch repair (MMR) complementation assay, the MMR activity of p.R107W was reduced to less than 20% compared to wild type (100%), which was similar to other pathogenic/likely pathogenic variants in the assay (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). Patient RNA analysis and in vitro minigene assays of the c.319C>T variant both demonstrated expression of alternatively spliced transcripts in addition to the full length PMS2 transcript, but this was not directly quantified (van der Klift HM et al. Mol. Genet. Genomic Med. 2015 Jul;3:327-45). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000465201	SCV000552039	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 107 of the PMS2 protein (p.Arg107Trp). This variant is present in population databases (rs188006077, gnomAD 0.002%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 25512458, 26110232, 27435373, 30702970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 127789). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 27435373). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115693	SCV000686190	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 107 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in mismatch repair activity, with less than 20% of wild type protein activity (PMID: 27435373). This variant has been reported in individuals with Lynch syndrome-associated cancers (PMID: 27435373; ClinVar SCV000187425.8). This variant has also been observed in trans with a PMS2 exon 10 deletion in an individual affected with autosomal recessive constitutional mismatch repair deficiency (PMID: 27435373), indicating that this variant contributes to disease. This variant has been identified in 3/236786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000586637	SCV000806214	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174801	SCV001338147	uncertain significance	not specified	2020-02-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.319C>T (p.Arg107Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Although the c.319C>T falls within exon 4, and 4/4 programs in Alamut predict that this variant does not affect normal splicing, splicing studies have shown that this variant promotes the expression of the alternative transcripts lacking exon 4 over full-length (FL) transcripts (van der Klift_2015). The alternative transcripts are also found in wt RNA, and, since the exact differences in the rate of expression of the FL and alternative transcripts could not be determined, the translational impact of this variant remains uncertain. The variant allele was found at a frequency of 1.3e-05 in 236786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.319C>T has been reported in the literature in individuals affected with or with a family history of Lynch Syndrome-spectrum cancers, as well as in at least one patient with suspected CMMRD who carried a second pathogenic variant (van der Klift_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one patient with endometrial cancer, co-occurrence with another pathogenic variant was reported (POLE, p.R563*), providing supporting evidence for a benign role (Stelloo_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003467056	SCV004207885	likely pathogenic	Lynch syndrome 4	2022-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586637	SCV004219001	likely pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000013 (3/236786 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families affected with a Lynch syndrome associated cancer (PMIDs: 25512458 (2015), 27742654 (2017), 30702970 (2019)) and in an individual affected with CMMRD (PMID: 27435373 (2016)). Functional assays have shown this variant causes aberrant splicing and deficient mismatch repair activity (PMIDs: 26247049 (2015), 27435373 (2016)). Based on the available information, this variant is classified as likely pathogenic.