Submissions for variant NM_000535.7(PMS2):c.710A>T (p.Gln237Leu)

dbSNP: rs587780061

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212850	SCV000149611	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with biallelic RNU4ATAC variants and a diagnosis of Roifman syndrome; however, information regarding family history of cancer was not provided (PMID: 26522830); This variant is associated with the following publications: (PMID: 11574484, 26522830)
Ambry Genetics	RCV000115702	SCV000214919	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-30	criteria provided, single submitter	clinical testing	The c.710A>T (p.Q237L) alteration is located in exon 7 (coding exon 7) of the PMS2 gene. This alteration results from a A to T substitution at nucleotide position 710, causing the glutamine (Q) at amino acid position 237 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226619	SCV000285150	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 237 of the PMS2 protein (p.Gln237Leu). This variant is present in population databases (rs587780061, gnomAD 0.009%). 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: 127795). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Counsyl	RCV000662456	SCV000784934	uncertain significance	Lynch syndrome 4	2017-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765963	SCV000897384	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	RCV000115702	SCV000909672	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with leucine at codon 237 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 not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified 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	RCV000212850	SCV002774695	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212850	SCV003917139	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PMS2: PM2
Myriad Genetics, Inc.	RCV000662456	SCV004019852	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662456	SCV004207843	uncertain significance	Lynch syndrome 4	2023-05-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806066	SCV005429635	uncertain significance	Lynch syndrome	2024-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with leucine at codon 237 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/24222 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212850	SCV001550122	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Gln237Leu variant was not identified in the literature but was identified in dbSNP (ID: rs587780061) as “with Uncertain significance allele”; in the ClinVar and Clinvitae databases as uncertain significance by GeneDx, Ambry Genetics and Invitae. The variant was not identified in the GeneInsight –COGR, Cosmic, MutDB; Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, or Insight Hereditary tumors databases. The variant was not identified in the 1000 Genomes or in the NHLBI GO Exome Sequencing Projects. The variant was identified in control databases in 1 of 24222 chromosomes at a frequency of 0.00004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 11546 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gln237 residue is conserved in mammals but not in more distant organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.