Submissions for variant NM_000535.7(PMS2):c.1242C>T (p.Asp414=)

gnomAD frequency: 0.00025  dbSNP: rs142839559

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166893	SCV000217710	likely benign	Hereditary cancer-predisposing syndrome	2014-12-08	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	RCV001079179	SCV000285056	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166893	SCV000686110	likely benign	Hereditary cancer-predisposing syndrome	2016-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589485	SCV000697288	benign	not specified	2022-06-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589485	SCV001469603	benign	not specified	2019-12-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001358483	SCV001844341	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166893	SCV002529775	likely benign	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358483	SCV001554229	likely benign	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Asp414= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs142839559) as "With Likely benign allele" and in ClinVar (classified as benign by Invitae; and as likely benign by Ambry Genetics, Color and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 37 of 277098 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 27 of 24012 chromosomes (freq: 0.001, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6458 chromosomes (freq: 0.0003), Latino in 6 of 34414 chromosomes (freq: 0.0002), and European in 2 of 126636 chromosomes (freq: 0.00002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp414= 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.