Submissions for variant NM_000535.7(PMS2):c.88C>A (p.Gln30Lys)

gnomAD frequency: 0.00003  dbSNP: rs141577476

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227509	SCV000285159	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-11-28	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 30 of the PMS2 protein (p.Gln30Lys). This variant is present in population databases (rs141577476, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 237929). 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	RCV001018478	SCV001179723	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	The p.Q30K variant (also known as c.88C>A), located in coding exon 2 of the PMS2 gene, results from a C to A substitution at nucleotide position 88. The glutamine at codon 30 is replaced by lysine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphoblastic leukemia (ALL) (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.
GeneDx	RCV001550352	SCV001770665	uncertain significance	not provided	2021-09-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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: 11574484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001550352	SCV002046217	uncertain significance	not provided	2020-09-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001018478	SCV002053226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 30 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 reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 3/245770 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.
All of Us Research Program, National Institutes of Health	RCV003998797	SCV004842168	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 30 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 reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 3/245770 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.
Baylor Genetics	RCV004567719	SCV005056434	uncertain significance	Lynch syndrome 4	2024-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742343	SCV005346306	uncertain significance	PMS2-related disorder	2024-08-13	no assertion criteria provided	clinical testing	The PMS2 c.88C>A variant is predicted to result in the amino acid substitution p.Gln30Lys. This variant was reported as a variant of uncertain significance in a pediatric cancer patient with acute lymphoblastic leukemia (Table S4a, Zhang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/237929/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.