Submissions for variant NM_000535.7(PMS2):c.353+6A>G

gnomAD frequency: 0.00006  dbSNP: rs376449640

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226224	SCV000285130	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581327	SCV000691068	likely benign	Hereditary cancer-predisposing syndrome	2016-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507750	SCV000697361	uncertain significance	not specified	2022-09-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.353+6A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 6e-05 in 234546 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.353+6A>G has been reported in the literature in one individual affected with colorectal cancer (Yurgelun_2017). The report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1), likely benign (n=3) and VUS (n=6). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000663107	SCV000786224	uncertain significance	Lynch syndrome 4	2018-03-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000586664	SCV000806215	likely benign	not provided	2017-08-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586664	SCV000888415	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an affected individual with colorectal cancer (PMID: 28135145 (2017)). The frequency of this variant in the general population, 0.00011 (14/124264 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect PMS2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000586664	SCV001908734	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28135145)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798733	SCV002042806	uncertain significance	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000507750	SCV002069637	uncertain significance	not specified	2020-10-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change in intron 4, c.353+6A>G. This sequence change has been described in the gnomAD database with a frequency of 0.011% in the European sub-population (dbSNP rs376449640). The c.353+6A>G change has been observed in the literature in one individual with colorectal cancer (PMID: 28135145). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs and is located in a domain of the PMS2 protein that is not known to be functional. It is possible that this sequence change represents a benign sequence change in the PMS2 gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to a disease phenotype cannot definitively be determined.
Sema4, Sema4	RCV000581327	SCV002530330	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663107	SCV004019825	likely benign	Lynch syndrome 4	2023-09-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Mayo Clinic Laboratories, Mayo Clinic	RCV000586664	SCV004223993	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	BP4, BP7
All of Us Research Program, National Institutes of Health	RCV003998791	SCV004824076	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535734	SCV001749842	not provided	Mismatch repair cancer syndrome 1		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.