ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1559C>T (p.Ala520Val) (rs63751300)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164554 SCV000215212 likely benign Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification;Structural Evidence
Invitae RCV000200307 SCV000254600 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 520 of the PMS2 protein (p.Ala520Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant (rs63751300) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been observed in individuals affected with colorectal cancer and suspected Lynch syndrome (PMID: 26232782, 25980754, 27601186). ClinVar contains an entry for this variant (Variation ID: 185185). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). An algorithm developed specifically for PMS2 suggests that this variant is likely to be tolerated (PMID: 22290698). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional 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.
Counsyl RCV000411039 SCV000488683 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000486349 SCV000565412 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1559C>T at the cDNA level, p. Ala520Val (A520V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant was observed in an individual with a personal history of Lynch-syndrome associated cancer and/or polyps who also carried a pathogenic MSH2 variant (Yurgelun 2015). PMS2 Ala520Val has been observed in both invasive breast carcinomas and normal breast tissue, and was thus considered a polymorphism in a study by Balogh et al. (2006). Although this variant was observed in 1000 Genomes, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. PMS2 Ala520Val occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011, UniProt). Published and internal in silico analyses predict that this variant is unlikely to alter protein structure or function (Ali 2012). Based on currently available evidence, it is unclear whether PMS2 Ala520Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000515358 SCV000611420 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000164554 SCV000903023 likely benign Hereditary cancer-predisposing syndrome 2016-04-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781744 SCV000920033 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1559C>T (p.Ala520Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function as well as an algorithm developed specifically for PMS2 (Ali, 2012). The variant allele was found at a frequency of 7.2e-05 in 20/277030 control chromosomes, predominantly in Latinos subcohort (10/34416 chrs tested). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism. The c.1559C>T has been reported in the literature in several affected individuals, and co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.2210+1G>A; PMS2 c.1492del11), providing supporting evidence for a benign role (Yurgelun, 2015; Nomura, 2015). In addition, the variant has been reported as benign polymorphism (Balogh, 2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4 VUS, 1 likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly 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.