Submissions for variant NM_000179.3(MSH6):c.4001+2T>C

dbSNP: rs267608131

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074969	SCV000108185	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration, >2 MSI-H, co-segregation with disease & absent in 1000 genomes
Ambry Genetics	RCV000491060	SCV000580113	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-15	criteria provided, single submitter	clinical testing	The c.4001+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 9 in the MSH6 gene. This alteration occurs at the 3' terminus of the MSH6 gene and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in several Danish HNPCC/Lynch syndrome families (Nilbert M et al. Fam. Cancer 2009;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat., 2010 Apr;120:777-82; Okkels H et al. Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7; Therkildsen C et al. Eur. J. Neurol., 2015 Apr;22:717-24). This variant has also been identified in probands whose HNPCC/Lynch syndrome-associated tumors demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000812440	SCV000952753	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-10-26	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed to segregate with disease in a Lynch syndrome family and has been observed in several individuals and families with suspected Lynch syndrome (PMID: 18566915, 21836479, 25648859, 22495361). ClinVar contains an entry for this variant (Variation ID: 89501). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 9) of the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267832	SCV002552373	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450986	SCV004189270	likely pathogenic	Lynch syndrome 5	2023-08-29	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.