ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.52A>G (p.Ile18Val) (rs63750123)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000034629 SCV000885990 benign not provided 2017-08-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132131 SCV000187201 benign Hereditary cancer-predisposing syndrome 2014-09-03 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034629 SCV000043441 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034629 SCV000510932 benign not provided 2016-07-29 criteria provided, single submitter clinical testing
Color RCV000132131 SCV000537374 benign Hereditary cancer-predisposing syndrome 2014-12-26 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076873 SCV000592919 uncertain significance Lynch syndrome 2014-12-11 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000613430 SCV000734570 benign Hereditary nonpolyposis colorectal cancer type 4 no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000076873 SCV000296936 benign Lynch syndrome 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000121853 SCV000171041 benign not specified 2013-11-12 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.
GeneKor MSA RCV000132131 SCV000821803 likely benign Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121853 SCV000248537 benign not specified 2016-09-13 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000613430 SCV000743786 likely benign Hereditary nonpolyposis colorectal cancer type 4 2016-02-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000613430 SCV000745850 benign Hereditary nonpolyposis colorectal cancer type 4 2015-05-08 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000034629 SCV000784713 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
ITMI RCV000121853 SCV000086055 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000076873 SCV000469747 likely benign Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000132131 SCV000679740 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034629 SCV000697371 benign not provided 2017-08-16 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.52A>G (p.Ile18Val) variant located in the Histidine kinase-like ATPase, C-terminal domain of the protein (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, a functional study indicates the variant does not affect MMR activity (Drost_2013. This variant was found in 2457/271244 control chromosomes (gnomAD) including 22 homozygotes at a frequency of 0.0090519, which is approximately 80 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. However, this observation needs to be cautiously considered because the sequencing technology (exome and genome sequencing) used cannot rule out the fact that the pseudogene could have been amplified. Several publications have cited the variant in affected individuals with Lynch Syndrome or related disorders, including reports of lack of cosegregation with disease in multiple families (Leongamornlert_2014 and Hendriks_2006). This variant also co-occurred with another pathogenic variant in a CRC patient and a suspected LS patient (Haraldsdottir_2017 and van der Klift_2016). In addition, in multiple internal LCA samples this variant was found to co-occur with another pathogenic or likely pathogenic variants such as PMS2 c.137G>T (p.Ser46Ile), MSH6 c.1634_1637delAAGA (p.Lys545fsX25), BRCA2 c.4647_4650delAGAG (p.Lys1549fsX18) MUTYH c.933+3A>C, MSH2 c.2038C>T (p.Arg680X) and PMS2 c.251-2A>T and MLH1 c.955G>T (p.Glu319X). Furthermore, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as likely benign/benign. Therefore due to the lack of cosegregation with disease, multiple co-occurrences with a pathogenic/likely pathogenic variant, and multiple clinical diagnostic laboratories classifying the variant as "likely benign/benign," the variant of interest has been classified as Benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000144650 SCV000108366 likely benign Lynch syndrome I 2014-10-10 reviewed by expert panel research MAF >1% in a specific ethnic group (European American)
Invitae RCV000524475 SCV000262414 benign Hereditary nonpolyposis colon cancer 2018-01-22 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000121853 SCV000691982 likely benign not specified no assertion criteria provided clinical testing
Pathway Genomics RCV000144650 SCV000189977 benign Lynch syndrome I 2014-10-17 no assertion criteria provided clinical testing
PreventionGenetics RCV000121853 SCV000806217 benign not specified 2016-12-19 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000132131 SCV000788117 benign Hereditary cancer-predisposing syndrome 2018-01-15 no assertion criteria provided clinical testing
Vantari Genetics RCV000132131 SCV000267077 benign Hereditary cancer-predisposing syndrome 2016-02-03 criteria provided, single submitter clinical testing

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