Submissions for variant NM_000179.3(MSH6):c.3173-1_3173del

dbSNP: rs587779256

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074812	SCV000108021	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon (also interrupts canonical acceptor splice site)
Ambry Genetics	RCV000567808	SCV000669999	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-11-13	criteria provided, single submitter	clinical testing	The c.3173-1_3173delGA variant spans the exon/intron boundary of coding exon 5 in the MSH6 gene. This variant results from the deletion of 2 nucleotides at positions c.3173-1 to c.3173. This variant has been identified as germline in conjunction with a somatic pathogenic MSH6 variant in a tumor that demonstrated high microsatellite instability with loss of MSH6 expression by immunohistochemistry (Ambry internal data). The nucleotide region encompassed by the deletion includes the canonical acceptor site, which is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822708	SCV000963522	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-23	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 4 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). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 89347). This variant has not been reported in the literature in individuals affected with MSH6-related conditions.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985841	SCV001134423	pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Myriad Genetics, Inc.	RCV003450960	SCV004189316	likely pathogenic	Lynch syndrome 5	2023-08-22	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.
Baylor Genetics	RCV003460679	SCV004198111	likely pathogenic	Endometrial carcinoma	2022-11-23	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003460679	SCV005184168	pathogenic	Endometrial carcinoma	2024-08-07	criteria provided, single submitter	clinical testing