ClinVar Genomic variation as it relates to human health

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 p.R211Q variant (also known as c.632G>A), located in coding exon 6 of the PMS2 gene, results from a G to A substitution at nucleotide position 632. The arginine at codon 211 is replaced by glutamine, an amino acid with highly similar properties. This alteration was seen in a patient diagnosed with ovarian cancer at age 72 (Kraus C. et al. Int. J. Cancer. 2017 Jan;140(1):95-102). This alteration was also seen in two patients diagnosed with colon cancer from Denmark and/or Sweden (Okkels H et al. Genet Test Mol Biomarkers, 2019 Sep;23:688-695). Additionally, this alteration was identified in an individual diagnosed with small bowel cancer at 51. (Wang Q et al. J Med Genet, 2020 07;57:487-499).This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Observed in individuals with a personal or family history including colorectal, ovarian, breast, and other cancers (PMID: 27616075, 31433215, 32628757, 31992580, 32885271); 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: 33471991, 31433215, 27499925, 27616075, 31992580, 32628757, 32885271, 36243179, 11574484)

Variant summary: The PMS2 c.632G>A (p.Arg211Gln) variant causes a missense change involving the alteration of a conserved nucleotide located in the Ribosomal protein S5 domain 2-type fold (IPR020568) (InterPro). 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). This variant has been reported and classified as a VUS in one ovarian cancer patient without strong evidence for or against pathogenicity (Kraus_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

This missense variant replaces arginine with glutamine at codon 211 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and ovarian cancer (PMID: 27616075, 31433215, 31992580, 32628757). This variant has also been reported in individuals affected with breast cancer (PMID: 32885271, 33471991, 34359559), as well as ten healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 12/282866 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 sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 211 of the PMS2 protein (p.Arg211Gln). This variant is present in population databases (rs587781934, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 27616075, 31433215, 31992580, 32628757). ClinVar contains an entry for this variant (Variation ID: 141683). 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 expected to disrupt PMS2 protein function with a positive 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.

This missense variant replaces arginine with glutamine at codon 211 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and ovarian cancer (PMID: 27616075, 31433215, 31992580, 32628757). This variant has also been reported in individuals affected with breast cancer (PMID: 32885271, 33471991, 34359559), as well as ten healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 12/282866 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.

PMS2: PM2, PS4:Supporting, BP1, BS3:Supporting

The PMS2 p.Arg211Gln variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Zhejiang University Database, or the Mismatch Repair Genes Variant Database. The variant was identified in dbSNP (ID: rs587781934) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics), Clinvitae, and the Insight Hereditary Tumors Database (effect unknown). The variant was identified in control databases in 12 of 277218 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: African in 1 of 24024 chromosomes (freq: 0.00004), European in 11 of 126724 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg211 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.