Submissions for variant NM_000535.7(PMS2):c.1211C>G (p.Pro404Arg)

gnomAD frequency: 0.00004  dbSNP: rs536111818

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132334	SCV000187422	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	The p.P404R variant (also known as c.1211C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1211. The proline at codon 404 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a family who met Amsterdam I criteria (Martin-Morales L et al. PLoS One 2018 Sep;13:e0203885). In an analysis of 71 colorectal cancer patients, this alteration was detected in a suspected HNPCC/Lynch syndrome patient whose tumor demonstrated microsatellite instability (MSI-H) (Mueller J et al. Cancer Res. 2009 Sep;69:7053-61). This alteration has also been reported in a Brazilian individual with colorectal cancer whose tumor showed loss of MLH1 and PMS2 on immunohistochemistry analysis and whose family met Amsterdam I criteria (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). Another study reported this alteration in an individual who was found to have a single juvenile polyp removed at age 48, and this alteration was classified as likely not pathogenic (Jelsig AM et al. Scand. J. Gastroenterol. 2016 Sep;51:1118-25). This amino acid position is poorly 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.
Invitae	RCV000168006	SCV000218657	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000479344	SCV000565842	uncertain significance	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history suspicious for Lynch syndrome, including those whose tumors revealed microsatellite instability or absence of PMS2 protein on immunohistochemistry (Mueller et al., 2009; Carneiro da Silva et al., 2015; Yurgelun et al., 2015; Martin-Morales et al., 2018); 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: 19690142, 25980754, 26437257, 27146957, 28874130, 30256826)
Color Diagnostics, LLC DBA Color Health	RCV000132334	SCV000686108	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 404 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 individuals affected with Lynch syndrome-associated cancer (PMID: 25980754, 26437257, 28874130), breast cancer (PMID: 36200007), or juvenile polyposis (PMID: 27146957). This variant has been identified in 24/281242 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.
PreventionGenetics, part of Exact Sciences	RCV003389704	SCV000806167	uncertain significance	PMS2-related disorder	2022-09-09	criteria provided, single submitter	clinical testing	The PMS2 c.1211C>G variant is predicted to result in the amino acid substitution p.Pro404Arg. This variant has been reported in patients with suspected Lynch syndrome (Mueller et al. 2009. PubMed ID: 19690142; Jelsig et al. 2016. PubMed ID: 27146957 ). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6027185-G-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142875/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479344	SCV001134576	uncertain significance	not provided	2023-04-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00033 (10/30614 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with or suspected of being affected with Lynch syndrome (PMID: 19690142 (2009), 25980754 (2015), 26437257 (2015), and 28874130 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000987836	SCV001137305	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193252	SCV001361980	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1211C>G (p.Pro404Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 249858 control chromosomes. The observed variant frequency is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Non-Polyposis Colon Cancer phenotype (7.1e-05), however this data should be cautiously interpreted as PMS2 has highly homologous pseudogenes. c.1211C>G has been reported in the literature in individuals with suspected Lynch Syndrome and LS-associated cancers as well as breast cancer (daSilva_2015, Jelsig_2016, Kraus_2015, Mueller_2009, Rossi_2017, Yurgelun_2015), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000132334	SCV002529770	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000987836	SCV002584765	uncertain significance	Lynch syndrome 4	2022-07-26	criteria provided, single submitter	clinical testing	The PMS2 c.1211C>G (p.Pro404Arg) missense change has a maximum subpopulation frequency of 0.033% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer and/or Lynch syndrome (PMID: 19690142, 25980754, 26437257, 28135145, 28874130, 30256826). In one of these individuals the tumor demonstrated microsatellite instability (PMID: 19690142) and in a different individual the tumor revealed loss of the MLH1/PMS2 complex (PMID: 26437257). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000987836	SCV004205392	uncertain significance	Lynch syndrome 4	2023-10-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193252	SCV004243284	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998143	SCV004839832	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 404 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). 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 (PMID: 25980754, 26437257, 28874130) or juvenile polyposis (PMID: 27146957). This variant has been identified in 24/281242 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000479344	SCV001549083	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Pro404Arg variant was identified in 3 of 4424 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal cancer and a history of Lynch syndrome–associated cancer and/or polyps and was not identified in 368 control chromosomes from healthy individuals (Mueller 2009, Rossi 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs536111818) as with uncertain significance allele and in the ClinVar and Clinvitae databases as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Color Genomics. In addition, the variant was listed 1X in the Insight Colon Cancer Gene Variant and in the Insight Hereditary Tumors databases. The variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, Zhejiang University, and Mismatch Repair Genes Variant databases; nor was it identified in the NHLBI GO Exome Sequencing Project. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004). The variant was identified in control databases in 22 of 276462 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23802 chromosomes (freq: 0.00004), Latino in 3 of 34416 chromosomes (freq: 0.00009), European Non-Finnish in 8 of 126236 chromosomes (freq: 0.00006), and South Asian in 10 of 30782 chromosomes (freq: 0.0003) while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Pro404 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
Genetic Services Laboratory, University of Chicago	RCV001193252	SCV003839889	uncertain significance	not specified	2022-11-25	no assertion criteria provided	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1211C>G, in exon 11 that results in an amino acid change, p.Pro404Arg. This sequence change has been previously described in individuals with colorectal cancer suspected Lynch syndrome, including some individuals whose tumors showed microsatellite instability or lack of PMS2 protein on immunohistochemistry (PMID: 19690142, 25980754, 26437257, 28874130, 30256826). This sequence change has been described in the gnomAD database with a global population frequency of 0.008% (dbSNP rs536111818). The p.Pro404Arg change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. The p.Pro404Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro404Arg change remains unknown at this time.