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
Color RCV000771124 SCV000902863 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Counsyl RCV000410446 SCV000487778 uncertain significance Lynch syndrome I 2015-12-01 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000410446 SCV000744280 uncertain significance Lynch syndrome I 2017-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000590535 SCV000292820 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2211-6C>A or IVS13-6C>A and consists of a C>A nucleotide substitution at the -6 position of intron 13 of the MSH2 gene. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant was identified in an individual with early-onset colorectal cancer, whose corresponding tumor was microsatellite stable with normal protein expression by immunohistochemistry, as well as in another individual undergoing hereditary cancer susceptibility testing (Kraus 2015, Yorczyk 2015). This variant was observed at an allele frequency of 0.02% (27/126564) in individuals of European ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MSH2 c.2211-6C>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000410446 SCV000745644 uncertain significance Lynch syndrome I 2015-11-08 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590535 SCV000696241 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2211-6C>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 16/121148 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00024 (16/66652), which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). Multiple publications have cited the variant in affected individuals, although with limited information. Kraus_2015 reports the variant in an affected male that fulfilled the revised Bethesda criteria and had normal IHC staining, whose tumor sequencing identified 2 nonsense mutations in the APC gene. UMD, a reputable database cites the variant in 1 individual with a classification of UV and indicates that the variant affects splicing, however, functional information is not provided. A German PhD dissertation indicates the variant was found in an individual that carried another pathogenic MLH1 variant, c.1851_1853delGAA (p.K618del - scored by LCA as DV) and lack protein expression of MLH1 and PMS2 and that the variant of interest did not affect splicing, however, functional evidence to support this does not seem to be presented in the dissertation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance-possibly benign."
Invitae RCV000197226 SCV000254395 likely benign Hereditary nonpolyposis colon cancer 2017-12-10 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

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