Submissions for variant NM_000535.7(PMS2):c.2559C>T (p.Ile853=)

dbSNP: rs371673459

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163176	SCV000213697	likely benign	Hereditary cancer-predisposing syndrome	2014-12-04	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	RCV000228797	SCV000285125	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589686	SCV000697354	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284328	SCV001470056	likely benign	not provided	2022-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001284328	SCV001858514	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000589686	SCV002550677	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492671	SCV004239597	likely benign	Breast and/or ovarian cancer	2023-03-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163176	SCV004358949	likely benign	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355440	SCV001550326	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Ile853= variant was not identified in the literature. The variant was identified in dbSNP (rs371673459) as “with uncertain significance allele” and ClinVar (classified as likely benign by Invitae and Ambry Genetics and uncertain significance by Integrated Genetics). The variant was identified in control databases in 2 of 203,794 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 89,196 chromosomes (freq: 0.00002), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Ile853= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.