ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2211-6C>A (rs267608003)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080259 SCV000254395 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-23 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 I 2015-12-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236903 SCV000601461 uncertain significance not specified 2017-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236903 SCV000696241 likely benign not specified 2021-02-01 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2211-6C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by published peer-reviewed functional studies. The UMD database cites the variant in 1 individual with a classification of UV and indicates that the variant affects splicing, however, a traceable functional evidence is not provided. The variant allele was found at a frequency of 0.0001 in 251186 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (0.0001 vs 0.00057), allowing no conclusion about variant significance. c.2211-6C>A has been reported in the literature in individuals undergoing multigene panel testing for cancer (example, Kraus_2015, Yorcyzk_2015). 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/Lynch syndrome. 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. Seven 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=5). Some submitters cite overlapping references utilized in the context of this evaluation. Based on the preponderance of evidence supporting a neutral outcome as outlined above, the variant was re-classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000410446 SCV000744280 uncertain significance Lynch syndrome I 2017-05-31 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000410446 SCV000745644 uncertain significance Lynch syndrome I 2015-11-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771124 SCV000902863 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing

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