Submissions for variant NM_000535.7(PMS2):c.949C>A (p.Gln317Lys)

dbSNP: rs143277125

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483849	SCV000566055	uncertain significance	not provided	2018-03-08	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.949C>A at the cDNA level, p.Gln317Lys (Q317K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln317Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Gln317Lys is located within the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Gln317Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538453	SCV000625711	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 317 of the PMS2 protein (p.Gln317Lys). This variant is present in population databases (rs143277125, gnomAD 0.007%). This missense change has been observed in individual(s) with advanced cancer of an unspecified type (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 418758). 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.
Ambry Genetics	RCV000566189	SCV000663475	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.Q317K variant (also known as c.949C>A), located in coding exon 9 of the PMS2 gene, results from a C to A substitution at nucleotide position 949. The glutamine at codon 317 is replaced by lysine, an amino acid with similar properties. 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	RCV000566189	SCV000686258	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 317 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 an individual affected with an unspecified advanced cancer (PMID: 28873162). This variant has been identified in 1/251288 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.
Fulgent Genetics, Fulgent Genetics	RCV000765958	SCV000897379	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483849	SCV001134618	uncertain significance	not provided	2019-01-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566189	SCV002530411	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	curation
Baylor Genetics	RCV003470533	SCV004205440	uncertain significance	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002269	SCV004839874	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 317 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 an individual affected with an unspecified advanced cancer (PMID: 28873162). This variant has been identified in 1/251288 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.