ClinVar Genomic variation as it relates to human health

Variant summary: PMS2 c.1717A>T (p.Thr573Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251368 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (7.6e-05 vs 0.00011), allowing no conclusion about variant significance. c.1717A>T has been reported in the literature in settings of multigene panel testing in individuals affected with Lynch Syndrome-associated cancers and/or polyps without strong evidence for pathogenicity (e.g. Tung_2015, Yurgelun_2015, Tsaousis_2019, Li_2020). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A co-occurrence with another pathogenic variant has been reported (MSH2 c.842C>G, p.Ser281X; Tung_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

In the published literature, this variant has been reported in Lynch syndrome (PMID: 25980754 (2015)) and breast cancer (PMIDs: 25186627 (2015), 17016615 (2006)). The variant was also identified in an individual with an unspecified cancer (PMID: 31391288 (2020)). The frequency of this variant in the general population, 0.00013 (4/30616 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is denoted PMS2 c.1717A>T at the cDNA level, p.Thr573Ser (T573S) at the protein level, and results in the change of a Threonine to a Serine (ACC>TCC). This variant has been identified in at least two individuals with a personal history of a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). Although this variant was observed in the Exome Sequencing Project, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. PMS2 Thr573Ser occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). Both in house in silico analyses and published computational models predict that this variant is unlikely to alter protein structure or function (Ali 2012). Based on currently available information, it is unclear whether PMS2 Thr573Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

The PMS2 c.1717A>T variant is predicted to result in the amino acid substitution p.Thr573Ser. This variant has been reported as a polymorphism in a breast cancer tumor sample, being present in 19 of 20 samples (Balogh et al. 2006. PubMed ID: 17016615). This variant has also been reported as a variant of uncertain significance in a patient with breast and ovarian cancer (Supporting Data, Tung et al. 2014. PubMed ID: 25186627) and in a study of individuals undergoing testing for hereditary cancer syndromes (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6026679-T-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/183997/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.