ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.614A>C (p.Gln205Pro) (rs587779342)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164809 SCV000215490 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-14 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, the in silico prediction for this alteration is inconclusive. 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 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 205 of the PMS2 protein (p.Gln205Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754, 27435373). It was also reported to co-occur with a pathogenic PMS2 variant in an individual with constitutional mismatch repair deficiency (PMID: 18602922). ClinVar contains an entry for this variant (Variation ID: 91361). This variant has been reported to affect PMS2 protein 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 Hereditary nonpolyposis colorectal cancer type 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 Health, Inc RCV000164809 SCV000691091 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-25 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 (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 Hereditary nonpolyposis colorectal cancer type 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.
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
Human Genetics - Radboudumc,Radboudumc RCV000485945 SCV001954185 uncertain significance not provided no assertion criteria provided clinical testing

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