Submissions for variant NM_000179.2(MSH6):c.3379_3438+5del (rs1553331676)

Total submissions: 5

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	2017-10-26	criteria provided, single submitter	clinical testing	The c.3379_3438+5del65 pathogenic mutation results in the removal of 65 nucleotides at positions 3379 to 3438+5 in coding exon 5 and extending into the intronic region downstream of coding exon 5 in the MSH6 gene. This deletion is expected to abolish the native splice donor site and has been identified in a Lynch syndrome family with concordant tumor testing data (isolated loss of MSH6) by our laboratory (Ambry internal data). This mutation has also been reported in the literature in an individual with colorectal cancer at age 38, with tumor testing data showing microsatellite instability and loss of MSH6 via immunohistochemistry (Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92). In addition to the clinical data available, 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 pathogenic.
Invitae	RCV001038331	SCV001201797	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-10-21	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18301448, Invitae). ClinVar contains an entry for this variant (Variation ID: 89377). 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. 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.
Color Health, Inc	RCV000490849	SCV001350203	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-06-26	criteria provided, single submitter	clinical testing