Submissions for variant NM_000535.7(PMS2):c.2240G>C (p.Arg747Thr)

gnomAD frequency: 0.00002  dbSNP: rs587782671

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132094	SCV000187158	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	The p.R747T variant (also known as c.2240G>C), located in coding exon 13 of the PMS2 gene, results from a G to C substitution at nucleotide position 2240. The arginine at codon 747 is replaced by threonine, an amino acid with similar properties. This variant has been reported in an individual with breast cancer and colon polyps (Shirts BH et al. Genet. Med. 2016 10;18:974-81). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000524462	SCV000255290	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 747 of the PMS2 protein (p.Arg747Thr). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with colon polyps (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 142721). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000195874	SCV000266220	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000195874	SCV000469716	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781753	SCV000920048	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2240G>C (p.Arg747Thr) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249696 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, and should be interpreted with caution as the sequencing technology used may not rule out pseudogene interference. c.2240G>C has been reported in the literature as a VUS in settings of multigene panel testing in at least one individual affected with colon polyps (e.g. Shirts_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985905	SCV001134590	uncertain significance	not provided	2018-11-24	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000985905	SCV002009102	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483270	SCV002776403	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-10-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781753	SCV004025103	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462032	SCV004207804	uncertain significance	Lynch syndrome 4	2023-06-21	criteria provided, single submitter	clinical testing