Submissions for variant NM_000535.7(PMS2):c.1733G>A (p.Arg578His)

dbSNP: rs63750770

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199546	SCV000254608	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000218135	SCV000274787	likely benign	Hereditary cancer-predisposing syndrome	2021-03-22	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.
Color Diagnostics, LLC DBA Color Health	RCV000218135	SCV000686160	likely benign	Hereditary cancer-predisposing syndrome	2020-03-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001544673	SCV001763847	uncertain significance	not provided	2024-07-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with prostate cancer (PMID: 29368341); This variant is associated with the following publications: (PMID: 29596542, 29368341)
Sema4, Sema4	RCV000218135	SCV002530224	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320596	SCV004025111	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462329	SCV004205342	uncertain significance	Lynch syndrome 4	2024-02-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491945	SCV004239590	uncertain significance	Breast and/or ovarian cancer	2023-01-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001544673	SCV005625886	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	The PMS2 c.1733G>A (p.Arg578His) variant has been reported in the published literature in an individual with breast cancer (PMID: 25186627 (2015)), in an individual with prostate cancer (PMID: 29368341 (2018)), in a tumor sample of an individual with colorectal cancer (PMID: 29596542 (2018)), and in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). The frequency of this variant in the general population, 0.00056 (17/30614 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV001544673	SCV005894128	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BS1