Submissions for variant NM_000251.3(MSH2):c.1906_2005+8del

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002815211	SCV003203379	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-06-07	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Ala636Pro) have been determined to be pathogenic (PMID: 12454801, 17101317, 18951462, 19101824, 21419771, 22102614, 23990280). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant results in the deletion of part of exon 12 (c.1906_2005+8del) of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Myriad Genetics, Inc.	RCV003455583	SCV004186652	likely pathogenic	Lynch syndrome 1	2023-08-04	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 3658675].