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

dbSNP: rs587779279

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074902	SCV000108114	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Invitae	RCV000791366	SCV000253780	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-16	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. 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 MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89434). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491917	SCV000580144	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The c.3647-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 8 of the MSH6 gene. This mutation has been reported 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 mutation has also been detected in a man with prostate cancer whose tumor showed loss of the MSH6 protein on immunohistochemistry (Dominguez-Valentin M et al. BMC Urol, 2016 Mar;16:15). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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.
Revvity Omics, Revvity	RCV001781398	SCV002017580	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001781398	SCV002552355	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV002467438	SCV002762827	pathogenic	Lynch syndrome 5	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_MOD, PM2_SUP, PP1
Myriad Genetics, Inc.	RCV002467438	SCV004189250	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001781398	SCV002034937	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001781398	SCV002035907	pathogenic	not provided		no assertion criteria provided	clinical testing