ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2187C>G (p.Leu729=) (rs373630535)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000127465 SCV000171037 benign not specified 2013-12-31 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 RCV000162439 SCV000212788 likely benign Hereditary cancer-predisposing syndrome 2014-06-20 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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 RCV001079494 SCV000252715 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000197459 SCV000257703 likely benign Lynch syndrome 2015-03-06 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000127465 SCV000596466 likely benign not specified 2016-06-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000127465 SCV000601840 likely benign not specified 2017-03-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590780 SCV000697340 benign not provided 2016-02-15 criteria provided, single submitter clinical testing Variant summary: The c.2187C>G variant affects a non-conserved nucleotide, resulting in no amino acid change. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 106/81156 control chromosomes (5 homozygotes) at a frequency of 0.0013061, which is about 11 times of maximal expected frequency of a pathogenic allele (0.0001136). Even considering the possibility that these occurrences may be from a PMS2 pseudogene, 5 homozygotes found in controls suggest this variant is benign. In addition, multiple clinical laboratories classified this variant as benign/likely benign. The variant of interest has not been evaluated for functional impact by in vivo/in vitro studies. Taken together, this variant was classified as benign.
Counsyl RCV000662897 SCV000785817 likely benign Hereditary nonpolyposis colorectal cancer type 4 2017-12-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000127465 SCV000806201 benign not specified 2017-02-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590780 SCV000888401 benign not provided 2018-03-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590780 SCV001155026 likely benign not provided 2020-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662897 SCV001322359 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-02-28 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355979 SCV001551019 benign Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Leu729= variant was not identified in the literature nor was it identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database. The variant was identified in dbSNP (ID: rs373630535) as “With other allele”, ClinVar (as benign by GeneDx and Invitae, and as likely benign by Ambry Genetics, Children's Hospital of Philadelphia, and University of Chicago), Clinvitae (3x), Insight Colon Cancer Gene Variant Database (1x with no classification), and Insight Hereditary Tumors Database. The variant was identified in control databases in 235 of 231538 chromosomes at a frequency of 0.0010 in the following populations: African in 1 of 13584 chromosomes (freq. 0.00007), Other in 2 of 5242 chromosomes (freq. 0.0004), Latino in 16 of 32934 chromosomes (freq. 0.0005), European (Non-Finnish) in 115 (7 homozygous) of 102664 chromosomes (freq. 0.001), European (Finnish) in 1 of 21426 chromosomes (freq. 0.00005), and South Asian in 100 (3 homozygous) of 29508 chromosomes (freq. 0.003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu729= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000590780 SCV001808383 likely benign not provided no assertion criteria provided clinical testing

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