ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.101G>T (p.Ser34Ile)

gnomAD frequency: 0.00005  dbSNP: rs370612538
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166613 SCV000217417 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-15 criteria provided, single submitter clinical testing The p.S34I variant (also known as c.101G>T), located in coding exon 2 of the PMS2 gene, results from a G to T substitution at nucleotide position 101. The serine at codon 34 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was reported in an individual diagnosed with pancreatic ductal adenocarcinoma (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000231923 SCV000285040 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 34 of the PMS2 protein (p.Ser34Ile). This variant is present in population databases (rs370612538, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, head and neck squamous cell carcinoma, and/or pancreatic ductal adenocarcinoma (PMID: 26689913, 32255556, 34326862). ClinVar contains an entry for this variant (Variation ID: 186945). 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.
GeneDx RCV000485924 SCV000565380 uncertain significance not provided 2023-07-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with head and neck squamous cell carcinoma, pancreatic cancer, or breast cancer (Lu et al., 2015; Cremin et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 32255556, 26689913, 11574484, 32571878, 33471991)
Color Diagnostics, LLC DBA Color Health RCV000166613 SCV000686089 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-08 criteria provided, single submitter clinical testing This missense variant replaces serine with isoleucine at codon 34 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individuals affected with head and neck squamous cell carcinoma (PMID: 26689913) and pancreatic ductal adenocarcinoma (PMID: 32255556). In a large case-control breast cancer study, this variant was reported in 5/60466 cases and 0/53461 unaffected controls (PMID: 33471991). This variant has been identified in 12/277184 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 RCV000780635 SCV000918066 uncertain significance not specified 2023-01-02 criteria provided, single submitter clinical testing Variant summary: PMS2 c.101G>T (p.Ser34Ile) results in a non-conservative amino acid change located in the ATPase domain (IPR003594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245786 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (4.1e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.101G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual with pancreatic ductal adenocarcinoma (PDAC) (example, Cremin_2020) and in the The Cancer Genome Atlas (TCGA) cohort (Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Izuhara_2020). This variant mostly retained the ATPase activity, while lowering affinity for ATP, and destabilized the structure. However, these findings do not allow convincing conclusions about the variant effect in-vivo. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485924 SCV001469597 uncertain significance not provided 2023-05-18 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual affected with pancreatic ductal adenocarcinoma (PDAC) (PMID: 32255556 (2020)), and as a somatic variant in a head and neck squamous cell carcinoma tumor sample (PMID: 26689913 (2015)). It has been reported in individuals with breast cancer in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). One functional analysis suggested that this variant may retain ATPase and DNA-binding abilities while disrupting the structure of the N-terminal domain, but additional functional studies are needed to ascertain the global effect of this variant on gene and gene product (PMID: 32571878 (2020)). The frequency of this variant in the general population, 0.00008 (10/125392 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4 RCV000166613 SCV002529745 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-02 criteria provided, single submitter curation
Baylor Genetics RCV003468789 SCV004207778 uncertain significance Lynch syndrome 4 2023-07-26 criteria provided, single submitter clinical testing

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