Submissions for variant NM_000179.3(MSH6):c.3379_3438+5del

dbSNP: rs1553331676

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074844	SCV000108056	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon (also interrupts canonical donor splice site)
GeneDx	RCV000214789	SCV000279555	pathogenic	not provided	2020-12-03	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in an individual with early onset colon cancer demonstrating microsatellite instability and loss of MSH6 protein expression (Steinke 2008); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 18301448)
Ambry Genetics	RCV000490849	SCV000580107	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	The c.3379_3438+5del65 pathogenic mutation results from a deletion of 65 nucleotides between positions 3379 and 3438+5 and involves the canonical splice donor site after coding exon 5 of the MSH6 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by immunohistochemistry (Ambry internal data; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92). 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 donor site. 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	RCV001038331	SCV001201797	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-09	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. Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 89377). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 18301448; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 5 (c.3379_3438+5del) 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).
Color Diagnostics, LLC DBA Color Health	RCV000490849	SCV001350203	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-06-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000214789	SCV003822216	pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450965	SCV004188216	pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered 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.