Submissions for variant NM_000535.7(PMS2):c.614A>C (p.Gln205Pro)

gnomAD frequency: 0.00001  dbSNP: rs587779342

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164809	SCV000215490	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-01	criteria provided, single submitter	clinical testing	The p.Q205P variant (also known as c.614A>C), located in coding exon 6 of the PMS2 gene, results from an A to C substitution at nucleotide position 614. The glutamine at codon 205 is replaced by proline, an amino acid with similar properties. This alteration was detected in trans with a mutation in PMS2 (c.1A>G) in an individual diagnosed with colon cancer at 20 years, duodenal cancer at 41 years, and lymphoma (age at diagnosis was not provided). The proband had a family history of brain tumors diagnosed in two siblings in their 30s and immunohistochemistry demonstrated loss of PMS2 protein expression in both tumor and adjacent normal tissue (Senter L et al. Gastroenterology. 2008 Aug;135(2):419-28). This alteration was also identified once in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). In an in vitro study, this alteration displayed a decrease (~50%) in relative repair efficiency compared to wild type (100%), but was not classified as repair deficient because it had significantly higher repair levels than a known PMS2 mutation (Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80). Based on an internal structural assessment, this alteration may result in generalized destabilization of the ATPase domain near the MSH2/MSH6 binding interface (Guarné A et al. EMBO J. 2001 Oct;20:5521-31; Groothuizen FS et al. Elife. 2015 Jul;4:e06744). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic, but may represent a reduced penetrance allele.
Invitae	RCV000524477	SCV000285143	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 205 of the PMS2 protein (p.Gln205Pro). This variant is present in population databases (rs587779342, gnomAD 0.0009%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency and clinical features of Lynch syndrome (PMID: 18602922, 25980754, 27435373). ClinVar contains an entry for this variant (Variation ID: 91361). 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: 2402700). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000409570	SCV000489243	uncertain significance	Lynch syndrome 4	2016-09-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000485945	SCV000567507	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of Lynch syndrome-associated tumors (Yurgelun 2015, van der Klift 2016); Published functional studies demonstrate repair efficiency significantly higher than that of a pathogenic control but compromised when compared to wild-type (Drost 2013); Reported to co-occur with a PMS2 pathogenic variant in an individual with lymphoma, early-onset colon cancer, and duodenal cancer for whom at least one tumor demonstrated loss of PMS2 expression on immunohistochemistry (Senter 2008); Not observed at significant frequency in large population cohorts (Lek 2016); 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: 20531397, 19283792, 26247049, 18709565, 21376568, 26333163, 27435373, 11574484, 27535533, 31447099, 18602922, 24027009, 25980754)
Color Diagnostics, LLC DBA Color Health	RCV000164809	SCV000691091	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 205 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). A functional study has shown that this variant causes partial reduction in DNA mismatch repair activity of PMS2 protein (PMID: 24027009). This variant has been reported in over ten individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; Clinvar SCV000285143.7, communication with an external laboratory). This variant has also been observed in compound heterozygous state with PMS2 c.1A>G (p.Met1?) in an individual affected with early-onset colon cancer, duodenal cancer, and lymphoma and a family history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). This variant has been identified in 2/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000409570	SCV000840046	likely pathogenic	Lynch syndrome 4	2017-11-03	criteria provided, single submitter	clinical testing	A heterozygous c.614A>C (p.Q205P) likely pathogenic variant in the PMS2 gene was detected in this individual. This variant has been previously described as disease-causing in mismatch repair cancer syndrome (PMID: 18602922, 25980754), an autosomal recessive cancer predisposition syndrome. In addition, functional studies have indicated that the p.Q205P change alters PMS2 enzymatic function (PMID: 24027009). Therefore, we consider this variant to be likely pathogenic.
Sema4, Sema4	RCV000164809	SCV002530369	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-01	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149758	SCV003838395	uncertain significance	Breast and/or ovarian cancer	2022-02-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409570	SCV004205463	likely pathogenic	Lynch syndrome 4	2023-09-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485945	SCV004219017	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals suspected of Lynch syndrome (PMIDs: 27435373 (2016), 25980754 (2015)). Functional studies showed inconclusive results regarding the variant's impact on protein function (PMID: 24027009 (2013)). The frequency of this variant in the general population, 0.000008 (2/251496 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997191	SCV004839952	likely pathogenic	Lynch syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 205 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). A functional study has shown that this variant causes partial reduction in DNA mismatch repair activity of PMS2 protein (PMID: 24027009). This variant has been reported in over ten individuals affected with Lynch syndrome-associated cancers (PMID: 25980754; Clinvar SCV000285143.7, communication with an external laboratory). This variant has also been observed in compound heterozygous state with PMS2 c.1A>G (p.Met1?) in an individual affected with early-onset colon cancer, duodenal cancer, and lymphoma and a family history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). This variant has been identified in 2/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV003997191	SCV005045771	likely pathogenic	Lynch syndrome	2021-08-23	criteria provided, single submitter	clinical testing	The c.614A>C (p.Gln205Pro) variant in the PMS2 gene is located on the exon 6 and is predicted to replace glutamine with proline at codon 205 (p.Gln205Pro). This variant has also been observed in compound heterozygous state with PMS2 c.1A>G (p.Met1?) in an individual affected with early-onset colon cancer, duodenal cancer, and lymphoma and a family history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20531397). The variant has also been identified in 2 unrelated individuals with Lynch syndrome (PMID: 25980754, 27435373). Experimental study showed reduction in mismatch repair efficiency and negative functional impact of the variant (PMID: 24027009). The variant has been reported in ClinVar (ID: 91361). The variant is rare in the general population according to gnomAD (2/251496). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.823). Therefore, the c.614A>C (p.Gln205Pro) variant of PMS2 has been classified as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357098	SCV001552449	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Gln205Pro variant was identified in 3 of 3510 proband chromosomes (frequency: 0.0009) from Dutch, American and multinational individuals or families with Lynch syndrome or suspected hereditary cancer (Yurgelun 2015, van der Klift 2016, Senter 2008). The variant was also identified in dbSNP (ID: rs587779342) as “With Uncertain significance” allele, ClinVar and Clinvitae (classified as uncertain significance, reviewed by an expert panel 2013; submitters: uncertain significance by InSIGHT, Ambry Genetics, Counsyl and GeneDx; and likely pathogenic by Invitae 2017), Insight Colon Cancer Gene Variant Database (3x), and Insight Hereditary Tumors Database (3x) and was not identified in Genesight-COGR, Cosmic, Zhejiang Colon Cancer Database, and Mismatch Repair Genes Variant Database. The variant was identified in control databases in 1 of 246270 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017), being identified in 1 of 111720 European Non-Finnish individuals (frequency: 0000009). Functional assays for splicing and mismatch repair deficiency demonstrated no allele specific imbalance however mismatch repair efficiency was reduced (van der Klift 2016, Drost 2013). In silico analysis using the bioinformatics tool PON-MMR2 that looks at evolutionary conservation and amino acid features, found the variant benign (Niroula 2015). Senter et al (2008) identified the variant as co-occurring with a pathogenic PMS2 variant (c.1A>G, 5’ truncation) in 1 individual diagnosed with CRC at 20 years old, who had 2 siblings with brain cancer. The variants are described as biallelic suggesting that the c.614A>C variant has clinical significance. The p.Gln205 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Pro 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000485945	SCV001807510	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000485945	SCV001954185	uncertain significance	not provided		no assertion criteria provided	clinical testing