Submissions for variant NM_000535.7(PMS2):c.466A>G (p.Thr156Ala)

gnomAD frequency: 0.00001  dbSNP: rs786204206

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168296	SCV000218975	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 156 of the PMS2 protein (p.Thr156Ala). This variant is present in population databases (rs786204206, gnomAD 0.007%). This missense change has been observed in individual(s) with colon and breast cancer (PMID: 26320870, 35449176). ClinVar contains an entry for this variant (Variation ID: 188304). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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	RCV000485878	SCV000565383	uncertain significance	not provided	2024-02-26	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 colon and/or breast cancer (PMID: 26320870, 35449176); This variant is associated with the following publications: (PMID: 26423401, 23499907, 34626046, 35449176, 28767177, 11574484, 26320870)
Counsyl	RCV000662566	SCV000785168	uncertain significance	Lynch syndrome 4	2017-05-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022873	SCV001184658	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-29	criteria provided, single submitter	clinical testing	The p.T156A variant (also known as c.466A>G), located in coding exon 5 of the PMS2 gene, results from an A to G substitution at nucleotide position 466. The threonine at codon 156 is replaced by alanine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with colon and breast cancer at age 52 who also had a family history of cancer (Li J et al. J Mol Diagn, 2015 Sep;17:545-53). In one functional study, this alteration demonstrated reduced interaction with Akt kinase and increased PMS2 protein stability (Jia J et al. Cell. Signal., 2013 Jun;25:1498-504). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001022873	SCV001360036	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 156 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). A functional study has shown that the variant may result in the loss of phosphorylation induced by Akt kinase and increased stability of the PMS2 protein (PMID: 26423401). However, the clinical relevance of this observation is not known. This variant has been reported in an individual affected with colon and breast cancer (PMID: 26320870). This variant has been identified in 2/250722 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.
Myriad Genetics, Inc.	RCV000662566	SCV004019832	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000662566	SCV004205497	uncertain significance	Lynch syndrome 4	2023-08-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485878	SCV004219011	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected individuals with breast cancer (PMIDs: 26320870 (2015) and 35449176 (2022)), as well as colorectal cancer (PMID: 26320870 (2015)). Functional studies demonstrated reduced interaction with Akt kinase and increased stability of PMS2 protein (PMIDs: 23499907 (2013) and 26423401 (2016)). The frequency of this variant in the general population, 0.000008 (2/250722 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003995621	SCV004839969	uncertain significance	Lynch syndrome	2023-07-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 156 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Computational splicing tools suggest that this variant may not impact RNA splicing. Functional study has shown that the variant may result in the loss of phosphorylation induced by Akt kinase and increased stability of PMS2 protein (PMID: 26423401). However, clinical relevance of this observation is not known. This variant has been reported in an individual affected with colon and breast cancer (PMID: 26320870). This variant has been identified in 2/250722 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.