ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1510G>C (p.Glu504Gln) (rs368516768)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162805 SCV000213286 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing Conflicting evidence
Invitae RCV000524435 SCV000551992 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 504 of the PMS2 protein (p.Glu504Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs368516768, ExAC 0.005%). This variant has been reported in an individual with suspected Lynch syndrome and in an individual with colorectal cancer (PMID: 27435373, 28135145). ClinVar contains an entry for this variant (Variation ID: 91305). An experimental study has shown that this missense change does not affect PMS2 mismatch-repair activity in vitro (PMID: 27435373). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000483703 SCV000565408 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1510G>C at the cDNA level, p.Glu504Gln (E504Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has been observed in at least two individuals with colorectal cancer, one tumor was identified to have microsatellite instability (MSI-H) and loss of MLH1 and PMS2 proteins on mismatch repair immunohistochemistry (van der Klift 2016, Yurgelun 2017). However, van der Klift et al. (2016) also demonstrated that this variant was proficient in mismatch repair (MMR) activity in an in vitro MMR assay. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain based on insufficient evidence (Thompson 2014). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Glu504Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000162805 SCV000686132 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glutamine at codon 504 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). A functional study has shown that this variant does not impact mismatch-repair activity of the PMS2 protein (PMID: 27435373). This variant has been reported in an individual affected with a suspected Lynch syndrome (PMID: 27435373) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 9/282786 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780617 SCV000918036 uncertain significance not specified 2020-11-06 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1510G>C (p.Glu504Gln) results in a 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251388 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1510G>C, has been reported in the literature in individuals affected with suspected Lynch Syndrome or colorectal cancer (van der Klift_2016, Yurgelum_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication, van der Klift_2016, reports this variant was proficient in mismatch repair (MMR) activity, showing no damaging effect of this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354515 SCV001549152 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Glu504Gln variant was identified in 2 of 2908 proband chromosomes (frequency: 0.0007) from Dutch and American individuals or families with CRC or suspected hereditary cancer (van der Klift 2016,Yurgelun 2017). The variant co-occurred with MLH1 c.1744C>T, p.Leu582Phe in one patient and was found to show proficiency in a functional MMR assay (van der Klift 2016). The variant was identified in dbSNP (ID: rs368516768) “With other allele”, ClinVar (classified uncertain significance by InSIGHT, Invitae, GeneDx and Color, and likely benign by Ambry Genetics). The variant was also identified in control databases in 10 of 277148 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004) and European Non-Finnish in 9 of 126660 chromosomes (freq: 0.00007); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.2808_2811del, p.Ala938ProfsX21), increasing the likelihood the p.Glu504Gln variant does not have clinical significance in the context of hereditary breast cancer. The p.Glu504 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 the variant Gln impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 benign role for this variant. This variant is classified as likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.