Submissions for variant NM_000535.7(PMS2):c.738C>G (p.Pro246=)

gnomAD frequency: 0.00005  dbSNP: rs202094399

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206202	SCV000259771	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220152	SCV000274699	likely benign	Hereditary cancer-predisposing syndrome	2015-03-19	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.
Counsyl	RCV000409744	SCV000488364	likely benign	Lynch syndrome 4	2016-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001722117	SCV000520403	likely benign	not provided	2021-05-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220152	SCV000686232	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430291	SCV000697383	likely benign	not specified	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.738C>G alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 248942 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.738C>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000220152	SCV002530382	likely benign	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409744	SCV004019814	benign	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001722117	SCV004219025	likely benign	not provided	2023-09-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742330	SCV005362691	likely benign	PMS2-related disorder	2019-12-20	no assertion criteria provided	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).