ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1437C>G (p.His479Gln) (rs63750685)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081746 SCV000166374 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000121844 SCV000171026 benign not specified 2013-12-20 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 RCV000162366 SCV000212673 benign Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign);Other data supporting benign classification
University of Washington Department of Laboratory Medicine, University of Washington RCV000076809 SCV000266215 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121844 SCV000304718 benign not specified criteria provided, single submitter clinical testing
Color RCV000162366 SCV000691015 benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034615 SCV000693232 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034615 SCV000697296 benign not provided 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1437C>G (p.His479Gln) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome. This was confirmed by a functional study that showed through an in vitro MMR assay that the H479Q mutant protein has significantly higher relative repair efficiency than repair-deficient control E705K (70 vs 10%, p<0.01) (Drost_2013). This variant was found in 1284/277610 control chromosomes (8 homozygotes) at a frequency of 0.0046252, which is approximately 41 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in patients where it was often reported as a benign polymorphism. However, the frequency in ExAC and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its overlapping pseudogenes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Also, in multiple internal LCA samples this variant was found to co-occur with other pathogenic variants: MSH2, c.942+3A>T, BRCA1, c.68_69delAG (p.Glu23fsX17), and BRCA2, c.5946delT (p.Ser1982fsX22). One study reports the variant in a sample that was IHC-negative for MLH1 and PMS2 and with observed MLH1 hypermethylation (van der Klift_2016). Taken together, this variant is classified as benign.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625386 SCV000745193 benign Hereditary nonpolyposis colorectal cancer type 4 2016-04-14 criteria provided, single submitter clinical testing
Mendelics RCV000076809 SCV000838178 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000121844 SCV000860370 benign not specified 2018-03-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034615 SCV000885989 likely benign not provided 2017-10-20 criteria provided, single submitter clinical testing
Mendelics RCV000625386 SCV001137298 likely benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625386 SCV001322473 likely benign Hereditary nonpolyposis colorectal cancer type 4 2018-03-13 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034615 SCV000043429 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
ITMI RCV000121844 SCV000086043 not provided not specified 2013-09-19 no assertion provided reference population
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000625386 SCV000745844 benign Hereditary nonpolyposis colorectal cancer type 4 2015-11-08 no assertion criteria provided clinical testing

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