Submissions for variant NM_000535.7(PMS2):c.1629C>T (p.Asp543=)

gnomAD frequency: 0.00002  dbSNP: rs111673299

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163764	SCV000214345	likely benign	Hereditary cancer-predisposing syndrome	2015-01-20	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.
GeneDx	RCV000442516	SCV000514205	benign	not specified	2015-08-14	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.
Invitae	RCV000553585	SCV000625543	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163764	SCV001347264	likely benign	Hereditary cancer-predisposing syndrome	2017-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442516	SCV001372368	likely benign	not specified	2020-06-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995280	SCV004844168	likely benign	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354443	SCV001549060	likely benign	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Asp543= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs111673299) as "With Likely benign allele ", and in ClinVar (classified as benign by GeneDx; as likely benign by Ambry Genetics and Invitae). The variant was identified in control databases in 5 of 245568 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 111302 chromosomes (freq: 0.00002), East Asian in 2 of 17244 chromosomes (freq: 0.0001), Finnish in 1 of 22300 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, and South Asian populations. The p.Asp543= 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.