ClinVar Genomic variation as it relates to human health

Variant summary: PMS2 c.924G>C (p.Glu308Asp) results in a conservative amino acid change located in the S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251214 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.924G>C in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Co-occurrence with another likely pathogenic variant has been observed in our internal database (MSH2 c.2006-2A>T), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.924G>C, in exon 9 that results in an amino acid change, p.Glu308Asp. This sequence change does not appear to have been previously described in patients with PMS2-related disorders and has described in the gnomAD database with an overall frequency of 0.002% (dbSNP rs114185660). The p.Glu308Asp change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu308Asp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu308Asp change remains unknown at this time.

The frequency of this variant in the general population, 0.000025 (7/282574 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 32959997 (2020) and 33471991 (2021), See also LOVD (https://databases.lovd.nl/shared/variants/PMS2)). 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 missense variant replaces glutamic acid with aspartic acid at codon 308 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 32885271, 32959997, 33471991). This variant has been identified in 7/282574 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.

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 sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 308 of the PMS2 protein (p.Glu308Asp). This variant is present in population databases (rs114185660, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 32959997). ClinVar contains an entry for this variant (Variation ID: 185925). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or colorectal cancer (PMID: 32959997, 33471991, 32885271, 37965459); This variant is associated with the following publications: (PMID: 33471991, 32959997, 11574484, 32832836, 37965459, 32885271)

This missense variant replaces glutamic acid with aspartic acid at codon 308 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32959997). This variant has been identified in 7/282574 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.

The PMS2 p.Glu308Asp variant was not identified in the literature nor was it identified in the the following databases: COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs114185660) “With Uncertain significance allele”, ClinVar (classified uncertain significance by Ambry Genetics, Invitae and GeneDx), Clinvitae (3x), and in control databases in 7 of 276988 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24022 chromosomes (freq: 0.00008), Latino in 1 of 34414 chromosomes (freq: 0.00003), European Non-Finnish in 2 of 126686 chromosomes (freq: 0.00002), and South Asian in 2 of 30780 chromosomes (freq: 0.00007); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Glu308 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Asp to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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. This variant is classified as a variant of uncertain significance.

Variant interpreted as Uncertain significance and reported on 11-10-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.