Submissions for variant NM_000251.3(MSH2):c.2211-6C>A

gnomAD frequency: 0.00004  dbSNP: rs267608003

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080259	SCV000254395	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000590535	SCV000292820	uncertain significance	not provided	2020-06-30	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Identified in an individual with early-onset colorectal cancer, whose corresponding tumor was microsatellite stable with normal protein expression by immunohistochemistry (Kraus 2015) This variant is associated with the following publications: (PMID: 25318351, 25142776)
Counsyl	RCV000410446	SCV000487778	uncertain significance	Lynch syndrome 1	2015-12-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590535	SCV000601461	likely benign	not provided	2021-07-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236903	SCV000696241	likely benign	not specified	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: The variant allele was found at a frequency of 0.0001 in 251186 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the estimated maximum expected (MPAF) for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057), however, the variant was reported in the Swedish with a higher subpopulation frequency (i.e. 0.00057), which is similar to the MPAF, suggesting that the variant might be a benign polymorphism. c.2211-6C>A has been reported in the literature in individuals undergoing multigene panel testing for cancer (e.g. Kraus_2015, Yorcyzk_2015, Schubert_2019). One of these studies reported this variant as being observed in an affected male that fulfilled the revised Bethesda criteria, had a normal IHC staining, and whose tumor sequencing identified 2 nonsense mutations in the APC gene (Kraus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At-least one co-occurrence with another pathogenic variant(s) has been ascertained in the context of this evaluation (MLH1 c.1846_1848AAG , p.Lys618del, Keinath_2011, unpublished PhD thesis), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000771124	SCV000902863	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000771124	SCV002534460	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236903	SCV002552260	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771124	SCV002729601	likely benign	Hereditary cancer-predisposing syndrome	2019-07-25	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.
Myriad Genetics, Inc.	RCV000410446	SCV004018264	likely benign	Lynch syndrome 1	2023-03-17	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].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491944	SCV004239282	uncertain significance	Breast and/or ovarian cancer	2022-07-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997015	SCV004815713	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing