Submissions for variant NM_000535.7(PMS2):c.354-5C>G

gnomAD frequency: 0.00001  dbSNP: rs200591010

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212841	SCV000149603	uncertain significance	not provided	2021-07-09	criteria provided, single submitter	clinical testing	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with colorectal cancer (Yurgelun 2017); This variant is associated with the following publications: (PMID: 27535533, 28135145)
Ambry Genetics	RCV000115694	SCV000172940	likely benign	Hereditary cancer-predisposing syndrome	2020-01-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV001089084	SCV000253300	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000200031	SCV000469741	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115694	SCV000911082	likely benign	Hereditary cancer-predisposing syndrome	2015-07-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174967	SCV001338449	uncertain significance	not specified	2020-04-06	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.354-5C>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a cryptic 3' acceptor site. One predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251140 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.354-5C>G has been reported in the literature in an individual affected with colorectal cancer (Yurgelun_2017). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. 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, 3 classify as VUS while 2 classify as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798336	SCV002042807	uncertain significance	Breast and/or ovarian cancer	2019-08-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115694	SCV002530335	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212841	SCV004219005	uncertain significance	not provided	2022-09-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000044 (5/113424 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, it has been reported in an individual with colorectal cancer (PMID: 28135145 (2017)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PMS2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.