Submissions for variant NM_000535.7(PMS2):c.1732C>T (p.Arg578Cys)

dbSNP: rs63750534

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000662641	SCV000785328	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV000695037	SCV000823512	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 578 of the PMS2 protein (p.Arg578Cys). This variant is present in population databases (rs63750534, gnomAD 0.003%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency (CMMR-D)-associated tumors, breast cancer and colorectal cancer (PMID: 17557300, 31992580, 35449176). ClinVar contains an entry for this variant (Variation ID: 91311). 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 not expected to disrupt PMS2 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV001181986	SCV001347261	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 578 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with early onset colorectal cancer that displayed loss of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 31992580). This variant, alongside the variant c.1730_1731insA in cis, has also been reported in two siblings affected with constitutional mismatch repair deficiency who had another PMS2 variant c.137G>T (p.Ser46Ile) in trans (PMID: 17557300). This variant has been identified in 1/251352 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV001539070	SCV001756806	uncertain significance	not provided	2020-11-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer with MLH1 and PMS2 absent on immunohistochemistry (Wang 2020); This variant is associated with the following publications: (PMID: 17557300, 31992580)
Ambry Genetics	RCV001181986	SCV002713878	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The p.R578C variant (also known as c.1732C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1732. The arginine at codon 578 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with features consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome and biallelic PMS2 mutations (Auclair J et al, Hum. Mutat. 2007 Nov; 28(11):1084-90). This variant was also identified in an individual with colorectal cancer diagnosed at age 34 whose tumor demonstrated loss of MLH1 and PMS2 protein expression by IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499), and in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000662641	SCV004019921	uncertain significance	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320560	SCV004025113	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003320560	SCV004222918	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1732C>T (p.Arg578Cys) results in a non-conservative amino acid change in 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 4e-06 in 251352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1732C>T has been reported in the literature in association with another PMS2 variant reported as c.1730_1731insA [ later annotated as c.1730dupA (p.Arg578Alafs*3)] in two siblings affected with features of Constitutional Mismatch Repair Deficiency (CMMRD) (Auclair_2007). The authors reported the combined variation as p.Lys577fs attributed to a gene conversion event. A different paternally inherited putatively pathogenic PMS2 variant (c.137G>T, p.Ser461Ile) in trans with this combined variant was attributed to be the cause of CMMRD in this family. This variant has also been reported in isolation as a VUS in an individual with colorectal cancer diagnosed at age 34 and an absent staining for MLH1 and PMS2 with intact staining for MSH2 and MSH6 proteins by Immunohistochemistry (example, Wang_2020). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17557300, 31992580). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358575	SCV001554351	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Arg578Cys variant was identified in the literature, although the frequency of this variant in an affected population was not provided (Auclair 2007, Wernstedt 2012). The variant was also identified in dbSNP (ID: rs63750534) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight and Counsyl), Cosmic (3x in Endometrium, Large intestine, Skin), MutDB, and Insight Hereditary Tumors Database (1x class3). The variant was not identified in GeneInsight-COGR or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 1 of 246198 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in Latino population in 1 of 33582 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, European, or South Asian populations. The p.Arg578 residue is conserved across mammals and other organisms, and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.