Submissions for variant NM_000535.7(PMS2):c.1552G>A (p.Glu518Lys)

gnomAD frequency: 0.00001  dbSNP: rs376142390

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206422	SCV000259586	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 518 of the PMS2 protein (p.Glu518Lys). This variant is present in population databases (rs376142390, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25559809, 28466842). ClinVar contains an entry for this variant (Variation ID: 219612). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000213296	SCV000273555	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000587309	SCV000279141	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Observed in individuals with colon cancer (Chubb et al., 2015; Haraldsdottir et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25559809, 28466842)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587309	SCV000697301	uncertain significance	not provided	2016-07-25	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.1552G>A (p.Glu518Lys) variant involves the alteration of a non-conserved nucleotide and is present outside of the known functional domains. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/120582 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). This variant was observed in one patient with early onset colorectal cancer who had a family history of colorectal cancer and her tumor showed stable microsatellite (Chubb 2015). Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Fulgent Genetics, Fulgent Genetics	RCV000765957	SCV000897378	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213296	SCV000903147	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 28466842). A case-control study did not produce conclusive evidence for the association of this variant with colorectal cancer (PMID: 28466842). This variant has been identified in 5/251300 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587309	SCV001134581	uncertain significance	not provided	2019-03-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001160656	SCV001322471	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
All of Us Research Program, National Institutes of Health	RCV003997572	SCV004844185	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 518 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 28466842). A case-control study did not produce conclusive evidence for the association of this variant with colorectal cancer (PMID: 28466842). This variant has been identified in 5/251300 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.