Submissions for variant NM_000179.3(MSH6):c.458-1G>A

dbSNP: rs267608035

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075000	SCV000108218	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Color Diagnostics, LLC DBA Color Health	RCV001190339	SCV001357799	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-07-19	criteria provided, single submitter	clinical testing	This variant alters the canonical splice acceptor site in intron 2 of the MSH6 gene. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. Although RNA study has not been performed to confirm the prediction, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in trans with a pathogenic MSH6 co-variant in an individual with constitutional mismatch repair deficiency syndrome, whose rectal polyps showed absence of MSH6 protein by immunohistochemistry (PMID: 17259933). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001190339	SCV003997398	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	The c.458-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 3 of the MSH6 gene. This mutation has been confirmed in trans with a MSH6 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome (Scott RH et al. Nat Clin Pract Oncol, 2007 Feb;4:130-4). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003450988	SCV004189253	likely pathogenic	Lynch syndrome 5	2023-08-10	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.