Submissions for variant NM_000535.7(PMS2):c.883C>T (p.Arg295Trp)

gnomAD frequency: 0.00003  dbSNP: rs182246929

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123094	SCV000166394	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	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 295 of the PMS2 protein (p.Arg295Trp). This variant is present in population databases (rs182246929, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome, and individuals with a personal or family history of breast cancer (PMID: 25980754, 26824983, 29752822, 30093976, 30521064, 31360874, 35171259). ClinVar contains an entry for this variant (Variation ID: 135947). 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%. 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	RCV000165443	SCV000216172	likely benign	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000165443	SCV000292179	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 295 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 30521064) and breast and/or ovarian cancer (PMID: 26824983, 29752822, 30093976, 31742824, 32295625). This variant has also been identified in 22/282742 chromosomes in the general population by the Genome Aggregation Database (gnomAD), with 19/19948 of East Asian population alleles. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000487208	SCV000565973	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Observed in individuals with Lynch syndrome-associated cancer or polyps and in individuals with personal or family history of breast or ovarian cancer (Yurgelun et al., 2015; Lin et al., 2016; Chan et al., 2018; Jiang et al., 2019; Li et al., 2019; Shao et al., 2020; Van Marcke et al., 2020; Dorling et al., 2021; Yin et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 26824983, 29752822, 30521064, 30093976, 32295625, 31742824, 35171259, 33471991, 11574484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487208	SCV001470608	uncertain significance	not provided	2020-11-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267863	SCV002550731	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267863	SCV003922720	likely benign	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.883C>T (p.Arg295Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251352 control chromosomes, predominantly at a frequency of 0.00092 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 8-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 East Asian origin. The variant, c.883C>T, has been reported in the literature in individuals affected with Lynch Syndrome-associated cancers (Yurgelun_2015, Jiang_2018) or breast cancer (Lin_2016, Chan_2018, Toh_2018, Li_2019, Shao_2020, Dorling_2021), however it was also found in several unaffected controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV003460871	SCV004205357	uncertain significance	Lynch syndrome 4	2023-10-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997419	SCV004839889	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 295 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 30521064) and breast/ovarian cancer (PMID: 26824983, 29752822, 30093976, 31742824, 32295625). This variant has also been identified in 22/282742 chromosomes in the general population by the Genome Aggregation Database (gnomAD), with 19/19948 of East Asian population alleles. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GenomeConnect - Invitae Patient Insights Network	RCV003483489	SCV004228714	not provided	Lynch syndrome; Mismatch repair cancer syndrome 4		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-01-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.