Submissions for variant NM_000535.7(PMS2):c.831G>A (p.Thr277=)

gnomAD frequency: 0.00004  dbSNP: rs116481522

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164672	SCV000215339	likely benign	Hereditary cancer-predisposing syndrome	2014-05-23	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	RCV000203788	SCV000261394	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000436696	SCV000517853	benign	not specified	2015-07-21	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	RCV000164672	SCV000537506	likely benign	Hereditary cancer-predisposing syndrome	2015-11-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436696	SCV001338287	benign	not specified	2021-07-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000436696	SCV001470607	benign	not specified	2019-09-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164672	SCV002530393	likely benign	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000436696	SCV002550733	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003954972	SCV004771269	likely benign	PMS2-related disorder	2020-10-09	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	RCV003995358	SCV004839903	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354953	SCV001549687	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Thr277= variant was not identified in the literature. The variant was identified in ClinVar (classified as likely benign by Invitae, Ambry Genetics, and Color; and as benign by GeneDx). The variant was identified in control databases in 22 of 246186 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5484 chromosomes (freq: 0.0002), European Non-Finnish in 9 of 111646 chromosomes (freq: 0.00008), European Finnish in 1 of 22300 chromosomes (freq: 0.00005), and South Asian in 11 of 30782 chromosomes (freq: 0.0004), while it was not observed in the African, Latino, Ashkenazi Jewish, or East Asian populations. The p.Thr277= 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) 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.