Submissions for variant NM_000535.7(PMS2):c.1510G>C (p.Glu504Gln)

gnomAD frequency: 0.00006  dbSNP: rs368516768

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162805	SCV000213286	likely benign	Hereditary cancer-predisposing syndrome	2018-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000524435	SCV000551992	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 504 of the PMS2 protein (p.Glu504Gln). This variant is present in population databases (rs368516768, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or Lynch syndrome (PMID: 27435373, 28135145). ClinVar contains an entry for this variant (Variation ID: 91305). 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%. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 27435373). 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.
GeneDx	RCV000483703	SCV000565408	uncertain significance	not provided	2022-06-25	criteria provided, single submitter	clinical testing	Observed in at least two individuals with colorectal cancer (van der Klift 2016, Yurgelun 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27435373, 26333163, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000162805	SCV000686132	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 504 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). A functional study has shown that this variant does not impact mismatch-repair activity of the PMS2 protein (PMID: 27435373). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 27435373) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 9/282786 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780617	SCV000918036	uncertain significance	not specified	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1510G>C (p.Glu504Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251388 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1510G>C, has been reported in the literature in individuals suspected with Lynch Syndrome or colorectal cancer (van der Klift_2016, Yurgelum_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication, van der Klift_2016, reports this variant was proficient in mismatch repair (MMR) activity, showing no damaging effect of this variant. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000162805	SCV002530199	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483703	SCV002774691	uncertain significance	not provided	2021-07-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000062 (8/129134 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in at least two individuals with colorectal cancer (PMIDs: 27435373 (2016), 28135145 (2017)). Tumor analysis from an affected individual who also carried the MLH1 c.1744C>T variant showed microsatellite instability (MSI-H) and loss of MLH1 and PMS2 proteins (PMID: 27435373 (2016)). However, a further functional study indicated that this variant was proficient in mismatch repair activity in vitro (PMID: 27435373 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003460718	SCV004205337	uncertain significance	Lynch syndrome 4	2023-10-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354515	SCV001549152	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Glu504Gln variant was identified in 2 of 2908 proband chromosomes (frequency: 0.0007) from Dutch and American individuals or families with CRC or suspected hereditary cancer (van der Klift 2016,Yurgelun 2017). The variant co-occurred with MLH1 c.1744C>T, p.Leu582Phe in one patient and was found to show proficiency in a functional MMR assay (van der Klift 2016). The variant was identified in dbSNP (ID: rs368516768) “With other allele”, ClinVar (classified uncertain significance by InSIGHT, Invitae, GeneDx and Color, and likely benign by Ambry Genetics). The variant was also identified in control databases in 10 of 277148 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004) and European Non-Finnish in 9 of 126660 chromosomes (freq: 0.00007); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.2808_2811del, p.Ala938ProfsX21), increasing the likelihood the p.Glu504Gln variant does not have clinical significance in the context of hereditary breast cancer. The p.Glu504 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Gln impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.