Submissions for variant NM_000535.7(PMS2):c.2334C>T (p.Phe778=)

gnomAD frequency: 0.00004  dbSNP: rs768674294

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441565	SCV000515552	likely benign	not specified	2017-06-11	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.
Ambry Genetics	RCV000565443	SCV000663492	likely benign	Hereditary cancer-predisposing syndrome	2016-09-22	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	RCV000866193	SCV001007256	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477915	SCV004218983	likely benign	not provided	2022-09-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565443	SCV004359013	likely benign	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356216	SCV001551324	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Phe778= variant was not identified in the literature, nor was it identified in the following databases: COGR, Cosmic, Zhejiang University Database, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs768674294) as "With Likely benign allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics), and Clinvitae, databases. The variant was identified in control databases in 8 of 244988 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 3 of 33564 chromosomes (freq: 0.0001), European in 2 of 110826 chromosomes (freq: 0.00002), and South Asian in 3 of 30682 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Phe778= 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.