Submissions for variant NM_000535.7(PMS2):c.1320A>G (p.Pro440=)

gnomAD frequency: 0.00012  dbSNP: rs138697590

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082973	SCV000166369	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000127460	SCV000171025	benign	not specified	2014-03-18	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	RCV000162674	SCV000213121	likely benign	Hereditary cancer-predisposing syndrome	2014-09-17	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.
Color Diagnostics, LLC DBA Color Health	RCV000162674	SCV000537450	likely benign	Hereditary cancer-predisposing syndrome	2015-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127460	SCV000697293	benign	not specified	2020-09-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588011	SCV000888389	likely benign	not provided	2022-06-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588011	SCV002049328	likely benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000127460	SCV002066516	likely benign	not specified	2021-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162674	SCV002529783	likely benign	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356109	SCV001551181	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Pro440= variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs138697590) “With Likely benign allele”, ClinVar (classified with conflicting interpretations of pathogenicity: likely benign by Invitae, Ambry Genetics, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano; benign by GeneDx, and uncertain significance by Laboratory Corporation of America), Clinvitae (3x), and in control databases in 20 of 277136 chromosomes at a frequency of 0.00007, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24024 chromosomes (freq: 0.00008) and European Non-Finnish in 18 of 126664 chromosomes (freq: 0.0001) but not in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Pro440= 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 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.