Submissions for variant NM_000251.3(MSH2):c.2802G>A (p.Thr934=)

gnomAD frequency: 0.00009  dbSNP: rs150259097

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163660	SCV000214230	likely benign	Hereditary cancer-predisposing syndrome	2014-08-13	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.
Invitae	RCV001081812	SCV000284163	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000410886	SCV000488013	likely benign	Lynch syndrome 1	2015-12-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590245	SCV000601472	likely benign	not provided	2023-04-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163660	SCV000690099	likely benign	Hereditary cancer-predisposing syndrome	2016-02-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505974	SCV000696258	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000410886	SCV001135767	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590245	SCV001502304	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000590245	SCV001887390	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163660	SCV002534508	likely benign	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410886	SCV004018389	benign	Lynch syndrome 1	2023-03-22	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.
PreventionGenetics, part of Exact Sciences	RCV004537296	SCV004723415	likely benign	MSH2-related disorder	2019-06-17	criteria provided, single submitter	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).
All of Us Research Program, National Institutes of Health	RCV003997170	SCV004830020	likely benign	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590245	SCV000778618	likely benign	not provided	2017-10-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590245	SCV001552051	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Thr934= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs150259097) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, Counsyl and two other submitters; as uncertain significance by two submitters), UMD-LSDB (1x as unclassified variant ). The variant was identified in control databases in 25 of 273988 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 23584 chromosomes (freq: 0.0002), Latino in 3 of 34170 chromosomes (freq: 0.00009), European in 10 of 125066 chromosomes (freq: 0.00008), Finnish in 7 of 25714 chromosomes (freq: 0.0003), and South Asian in 1 of 30256 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Ashkenazi Jewish, and East Asian, populations. The p.Thr934= 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.