Submissions for variant NM_000179.3(MSH6):c.3647-2A>C

dbSNP: rs267608111

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074903	SCV000108115	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration (not quantified), >2 tumours with MSH6 protein loss, co-segregation with disease & absent in 1000 genomes.
CeGaT Center for Human Genetics Tuebingen	RCV001531316	SCV001746355	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2
Invitae	RCV001854283	SCV002235813	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	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 present in population databases (rs267608111, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10508506, 18566915, 21836479, 27601186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89435). 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	RCV002345375	SCV002618933	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	The c.3647-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 8 in the MSH6 gene. This variant has been identified in Norwegian families meeting Amsterdam II criteria and several individuals demonstrated isolated loss of MSH6 on immunohistochemistry in their Lynch associated tumors; however, the tumors had low microsatellite instability (MSI-L) (Wijnen J et al. Nat. Genet., 1999 Oct;23:142-4; Grindedal EM et al. Fam. Cancer, 2009 Oct;8:145-51 Hendriks YM et al. Gastroenterology, 2004 Jul;127:17-25; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). In one study, RT-PCR performed using a patient RNA sample reportedly demonstrated in-frame partial intron 7 retention with this variant, which would introduce a premature termination codon (Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85). This nucleotide position is highly conserved in available vertebrate species. 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV001531316	SCV003929833	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in aberrant splicing leading to a null allele in a gene for which loss of function is a known mechanism of disease (Sjursen et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Classified as pathogenic by a well-established clinical consortium and/or database; Identified in patients with personal and family history of Lynch-related tumors and segregated with disease in at least one family (Wijnen et al., 1999; Hendriks et al., 2004; Sjursen et al., 2010; Keranen et al., 2018); This variant is associated with the following publications: (PMID: 34445333, 32849802, 27601186, 20587412, 30572730, 29922827, 10508506, 18841495, 15236168)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001531316	SCV004024810	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003335091	SCV004043926	likely pathogenic	Lynch syndrome 5	2023-06-13	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.