Submissions for variant NM_000179.3(MSH6):c.3647-1G>C

dbSNP: rs587779279

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190323	SCV001357782	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 7 of the MSH6 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. However, different canonical splice site variants at this splice acceptor site, c.3647-1G>A and c.3647-2A>C, have been observed in affected members of Lynch syndrome families (PMID: 10508506, 15236168, 18566915, 18841495, 20587412, 21836479) and the c.3647-1G>A variant has been shown to cause out-of-frame splicing (PMID: 20587412). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001382590	SCV001581431	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-07-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the MSH6 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). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18566915, 21836479, Invitae). It has also been observed to segregate with disease in related individuals. 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001190323	SCV002613829	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The c.3647-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 8 of the MSH6 gene. Another alteration impacting the same donor site (c.3647-1G>A) has been detected in multiple individuals having features of or meeting clinical diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data; Nilbert M et al Fam. Cancer 2009;8(1):75-83; Therkildsen C et al Eur. J. Neurol. 2015 Apr;22(4):717-24; Klarskov L et al Am. J. Surg. Pathol. 2011 Sep;35(9):1391-9; Okkels H et al Appl. Immunohistochem. Mol. Morphol. 2012;20(5):470-7; Yurgelun MB et al Gastroenterology 2015;149(3):604-613). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003449622	SCV004189276	likely pathogenic	Lynch syndrome 5	2023-08-24	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.