Submissions for variant NM_000179.3(MSH6):c.3556+5_3556+8delinsCATTATTGTCAGG

dbSNP: rs2104510542

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kids Neuroscience Centre, Sydney Children's Hospitals Network	RCV001726531	SCV001571514	uncertain significance	Lynch syndrome 1		criteria provided, single submitter	clinical testing	Out-of-frame exon 6 skipping (r.3439_3556del) causes a frameshift encoding 8 missense amino acids and a premature termination codon (p.(Ala1147Valfs*9)). These transcripts are predicted to be targeted by nonsens e mediated decay (NMD). Any mis-spliced transcipts that escape NMD encode MSH6 protein lacking 215 amino acids from the C -terminus, including 180 amino acids from the MutS domain. Intron 6 retention (r.3556_3557ins[3556+1_3557-1]) causes a frameshift encoding 16 missense amino acids and a premature termination codon (p.(Glu1187Aspfs*17)). These transcripts are predicted to be targeted by NMD. Any mis spliced transcipts that escape NMD encode MSH6 protein lacking 174 amino acids from the C -terminus, including 139 amino acids from the MutS domain.
Ambry Genetics	RCV002456593	SCV002617795	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-14	criteria provided, single submitter	clinical testing	The c.3556+5_3556+8delGTTTins13 intronic variant, located in intron 6 of the MSH6 gene, results from a deletion of 4 nucleotides and the insertion of 13 nucleotides at nucleotide positions c.3556+5 to c.3556+8. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.