ClinVar Miner

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

dbSNP: rs143277125
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Total submissions: 8
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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.
Invitae RCV000538453 SCV000625711 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-26 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). 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.
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, 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.
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

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