Submissions for variant NM_000535.7(PMS2):c.2265C>T (p.Ile755=)

gnomAD frequency: 0.00001  dbSNP: rs145646046

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205449	SCV000260696	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000222777	SCV000273801	likely benign	Hereditary cancer-predisposing syndrome	2015-02-06	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.
CeGaT Center for Human Genetics Tuebingen	RCV001200526	SCV001371511	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526981	SCV001737772	likely benign	not specified	2021-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001200526	SCV001861959	likely benign	not provided	2020-09-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001200526	SCV004218981	benign	not provided	2023-07-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222777	SCV004359024	benign	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001200526	SCV001549074	likely benign	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Ile755= variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs145646046) as “With Likely benign allele”, ClinVar (as likely benign by Invitae and Ambry Genetics), and Clinvitae databases. The variant was identified in control databases in 24 of 244310 chromosomes (2 homozygous) at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 21 of 30634 chromosomes (freq: 0.0007) and European (Non-Finnish) in 3 of 110376 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ile755= 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, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing 5bp upstream of this variant, however, this information is not very predictive of pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although the available information suggests a benign role for this variant. This variant is classified as likely benign.