Submissions for variant NM_000535.7(PMS2):c.21G>C (p.Ser7=)

dbSNP: rs587780726

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123085	SCV000166383	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001711210	SCV000514188	likely benign	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24121792)
Ambry Genetics	RCV000566068	SCV000670757	likely benign	Hereditary cancer-predisposing syndrome	2015-11-06	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.
Color Diagnostics, LLC DBA Color Health	RCV000566068	SCV000686177	likely benign	Hereditary cancer-predisposing syndrome	2017-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436675	SCV000920055	likely benign	not specified	2019-08-30	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.21G>C (p.Ser7Ser) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 4e-06 in 250326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, there are no reports of c.21G>C in individuals with Lynch Syndrome and no experimental evidence demonstrating an impact of c.21G>C on protein function in the literature. Three other laboratories have submitted clinical significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV003997418	SCV004842183	likely benign	Lynch syndrome	2023-06-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355932	SCV001550961	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ser7= variant was not identified in the literature nor was it identified in the Genesight-COGR, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, Insight Hereditary Tumors Database, databases. The variant was identified in dbSNP (rs587780726) as likely benign allele, ClinVar (2x as likely benign), and Cosmic (2x) databases. The variant was identified in control databases in 1 of 245430 chromosomes at a frequency of 0.000004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ser7= 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.