Submissions for variant NM_000535.7(PMS2):c.2149G>A (p.Val717Met)

gnomAD frequency: 0.00072  dbSNP: rs201671325

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417397	SCV000149585	likely benign	not specified	2018-01-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000115676	SCV000187235	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	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.
Invitae	RCV001081398	SCV000255289	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000199450	SCV000296933	uncertain significance	Lynch syndrome	2015-10-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000411225	SCV000488729	uncertain significance	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000417397	SCV000601836	benign	not specified	2021-05-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515268	SCV000611422	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417397	SCV000697331	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2149G>A (p.Val717Met) results in a conservative amino acid change located in the C-terminal dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 237678 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome phenotype (7.1e-05), strongly suggesting that the variant is benign. c.2149G>A has been reported in the literature in individuals affected with Lynch Syndrome and other tumor phenotypes, however these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (example, Brea-Fernandez_2013, Borras_2013, Shirts_2015, Tung_2016, Yurgelun_2017, Pearlman_2017, Gonzalez-Acosta_2017, Chan_2018, Martin-Morales_2018, Delahunty_2022, Liccardo_2022). In at least one family, the variant did not segregate with the disease and co-occurred with another PMS2 variant (c.2444C>T). Functional studies by these authors showed that a different variant, c.2444C>T (p.S815L) caused a significant decrease in PMS2 and MLH1 protein expression (~15% of normal) and impaired MMR activity (~10% of normal). The variant of interest was also functionally analyzed and found not to significantly impair protein expression or MMR activity (Gonzalez-Acosta 2017), suggesting the variant of interest is likely not the driver of disease in the family. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Multiple other co-occurrences with pathogenic variants have been reported in the literature and observed at our laboratory (example, Pearlman_2017 - MLH1 c.589-2A>G; our laboratory - PMS2 c.1831dupA, p.Ile611fsX2), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 34371384, 23709753, 23837913, 30093976, 35263119, 28365877, 22703879, 35475445, 30256826, 27978560, 26845104, 26976419, 28135145). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 reporting the variant with conflicting assessments (benign/likely benign, n=14; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000417397	SCV000806199	likely benign	not specified	2019-05-23	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115676	SCV000822130	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492332	SCV000838172	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000199450	SCV000886459	likely benign	Lynch syndrome	2018-10-12	criteria provided, single submitter	clinical testing	The PMS2 variant designated as NM_000059.3:c.2149C>T (p.Val470Met) is classified as likely benign. This variant has been reported at a frequency of 1 in 70 individuals with Ashkenazi Jewish ancestry, and it is present in multiple ethnic populations (gnomad.broadinstitute.org). Variants present at this population frequency are unlikely to be associated with high penetrance hereditary cancer risk. This variant has also been seen in an individual with a co-occurring pathogenic mutation, adding evidence that it is benign. This variant is in ClinVar (Variation ID: 41709) and has been classified as likely benign by other clinical laboratories. Bayesian analysis integrating all of this data (Tavtigian et al, 2018) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter PMS2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034624	SCV001157937	likely benign	not provided	2023-03-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411225	SCV001324103	uncertain significance	Lynch syndrome 4	2018-09-17	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798066	SCV002042796	likely benign	Breast and/or ovarian cancer	2023-01-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034624	SCV002062733	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PMS2: PP2, BS2
Genetic Services Laboratory, University of Chicago	RCV000417397	SCV002069906	likely benign	not specified	2021-12-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115676	SCV002530264	benign	Hereditary cancer-predisposing syndrome	2020-07-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417397	SCV002550695	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115676	SCV004014971	benign	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411225	SCV004019875	likely benign	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115676	SCV004359542	likely benign	Hereditary cancer-predisposing syndrome	2017-06-20	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000199450	SCV005045935	likely benign	Lynch syndrome	2024-04-04	criteria provided, single submitter	clinical testing	The following ACMG criteria is used: BS1. The variant is reported once in gnomAD in homozygote state. Functional analysis indicates that the variant does not affect the function of PMS2 (PMID: 28365877)
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034624	SCV000043416	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000417397	SCV000691961	uncertain significance	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000199450	SCV001550478	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The PMS2 p.Val717Met variant was identified in 3 of 1014 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome and breast cancer (Brea-Fernandez 2014, Tung 2016). The variant was also identified in dbSNP (ID: rs201671325) as “With other allele”, ClinVar (7x, as likely benign by GeneDx, Invitae, as uncertain significance by Ambry Genetics, university of Washington, The Children Hospital of Philadelphia, Counsyl and Biescker Lab), Clinvitae (5x, as likely benign and uncertain significance), Cosmic (1x, as neutral in Haematopoitic and lymphoid tissue), Insight Colon Cancer Gene Variant Database (1x, unknown pathogenicity), Insight Hereditary Tumor Database (1x). The variant was identified in control databases in 184 of 263616 chromosomes at a frequency of 0.0007 in the following populations: African in 1 of 22146 chromosomes (freq. 0.000045), other in 6 of 6242 chromosomes (freq. 0.00096), Latino in 25 of 32882 chromosomes (freq. 0.00076), European in 81 of 119490 chromosomes (freq. 0.00067), Ashkenazi Jewish in 70 of 9812 chromosomes (freq. 0.007) and Finnish in 1 of 24924 chromosomes (freq. 0.00004),increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Consortium Feb 27, 2017). The p.Val717 residue is conserved in mammals 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. A Comprehensive functional study, including segregation data on two co-occurring in trans PMS2 variants (c.2149G>A, p.Val717Met and c.2444C>T, p.Ser815Lys) in a Spanish patient with family history of Lynch syndrome, concluded that p.Val717Met variant is likely benign and the p.Ser815Lys variant is likely pathogenic in this family (Gonzalez 2017).The variant is located within the MutL C-terminal, and dimerisation functional domain. 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 likely benign.