ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2149G>A (p.Val717Met) (rs201671325)

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Total submissions: 18
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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 Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV001081398 SCV000255289 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 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 Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000417397 SCV000601836 benign not specified 2017-05-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515268 SCV000611422 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 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 2020-07-30 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. One of two in-silico tools predict a benign 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 homozygotes. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), 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. 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 the c.2444C>T 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. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.589-2A>G; PMS2 c.1831dupA, p.Ile611fsX2; MLH1 c.589-2A>G), providing supporting evidence for a benign role. Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=6, VUS n=8). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000034624 SCV000806199 uncertain significance not provided 2016-11-22 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 RCV000199450 SCV000838172 uncertain significance Lynch syndrome 2018-07-02 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.
Mendelics RCV000411225 SCV001137282 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283707 SCV001157937 likely benign none provided 2020-01-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411225 SCV001324103 uncertain significance Hereditary nonpolyposis colorectal cancer type 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.
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.

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