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

gnomAD frequency: 0.00007  dbSNP: rs371342884

Total submissions: 16

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: 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	RCV000524473	SCV000252721	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000411614	SCV000487882	likely benign	Lynch syndrome 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 Diagnostics, LLC DBA Color Health	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	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000411614	SCV001326418	uncertain significance	Lynch syndrome 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
Genetic Services Laboratory, University of Chicago	RCV000431075	SCV002068647	likely benign	not specified	2019-03-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162488	SCV002530339	likely benign	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000431075	SCV002760385	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411614	SCV004019888	benign	Lynch syndrome 4	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
PreventionGenetics, part of Exact Sciences	RCV003925035	SCV004744039	likely benign	PMS2-related disorder	2019-10-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000076871	SCV004842115	benign	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing