ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.384G>A (p.Ser128=) (rs371342884)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076871 SCV000108273 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous variant with no effect on splicing or mRNA stability
Ambry Genetics RCV000162488 SCV000212864 likely benign Hereditary cancer-predisposing syndrome 2015-04-28 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 RCV000524473 SCV000252721 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-01 criteria provided, single submitter clinical testing
Counsyl RCV000411614 SCV000487882 likely benign Hereditary nonpolyposis colorectal cancer type 4 2015-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000431075 SCV000514192 benign not specified 2015-06-12 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.
Color Health, Inc RCV000162488 SCV000686200 benign Hereditary cancer-predisposing syndrome 2016-05-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000431075 SCV000918058 likely benign not specified 2018-06-18 criteria provided, single submitter clinical testing Variant summary: PMS2 c.384G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.9e-05 in 121588 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, the region is highly homologous to PMS2 pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference making ExAC and gnomAD data unreliable for assessing variant frequency. c.384G>A has been reported in the literature in an individual affected with Lynch Syndrome, however in this case a co-occurring pathogenic variant (PMS2 c.164-2A>G) was also present (in cis), providing supporting evidence for a benign role (Borras 2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000411614 SCV001137326 likely benign Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411614 SCV001326418 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-04-27 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262172 SCV001439946 benign Breast neoplasm 2019-01-01 criteria provided, single submitter clinical testing

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