ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1662-2A>G (rs267607971)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000076225 SCV000919688 pathogenic Lynch syndrome 2017-10-10 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1662-2A>G variant involves the alteration of a conserved intronic nucleotide and 4/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 245384 control chromosomes (gnomAD). Multiple publications have cited the variant in HNPCC patients (Bonadona_2011, Rossi_2017, Wang_2006) . Multiple reputable databases classified this variant as likely pathogenic/pathogenic. In addition, another variant at this position, c.1662-2A>C has been reported and cited as "pathogenic". Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076225 SCV000107249 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Interrupts canonical acceptor splice site
Invitae RCV000560516 SCV000625295 pathogenic Hereditary nonpolyposis colon cancer 2017-07-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families affected with Lynch syndrome (PMID: 16810763, 21642682). ClinVar contains an entry for this variant (Variation ID: 90728). A different variant affecting this nucleotide (c.1662-2A>C) has been determined to be pathogenic (PMID: 18566915, 24090359). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.

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