Submissions for variant NM_000251.3(MSH2):c.287G>A (p.Arg96His)

gnomAD frequency: 0.00004  dbSNP: rs63750002

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076555	SCV000107584	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics	RCV000164188	SCV000214808	likely benign	Hereditary cancer-predisposing syndrome	2019-02-01	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	RCV000524401	SCV000253157	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001719812	SCV000516099	likely benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 9311737, 18547406, 12547705, 12414824, 15340264, 22949387, 17074586, 7726159, 20176959, 22045683, 27266541)
Color Diagnostics, LLC DBA Color Health	RCV000164188	SCV000685076	likely benign	Hereditary cancer-predisposing syndrome	2015-11-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000662472	SCV000784966	likely benign	Lynch syndrome 1	2017-02-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000662472	SCV001135697	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442211	SCV001339206	likely benign	not specified	2020-03-30	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.287G>A (p.Arg96His) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.287G>A has been reported in the literature together with an MSH2 frameshift variant in a family affected with Lynch Syndrome, authors noted that the variant of interest did not segregate with the disease (Wijnen_1995). In addition, a co-occurrence with a (likely) pathogenic variant has also been reported (RAD51C c.1026+5_1026+7delGTA; in an LCA internal sample), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no effect on MMR activity for this variant (Martinez_2010, Houlleberghs_2016). Six submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar without evidence for independent evaluation, and all of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV000662472	SCV004018365	likely benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].