Submissions for variant NM_000179.3(MSH6):c.3556+2T>G

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002339752	SCV002618764	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-03	criteria provided, single submitter	clinical testing	The c.3556+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 6 in the MSH6 gene. This variant has been identified in an individual whose Lynch syndrome associated tumor demonstrated isolated loss of MSH6 expression by immunohistochemistry and family history met Amsterdam II criteria (Ambry internal data). 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). In addition to the clinical data from our internal cohort, 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 a disease-causing mutation.
Myriad Genetics, Inc.	RCV003454120	SCV004189269	likely pathogenic	Lynch syndrome 5	2023-08-24	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017924	SCV004848380	likely pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The c.3556+2T>G variant in MSH6 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss-of-function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome based upon predicted impact to the protein and absence in controls. ACMG/AMP criteria applied: PVS1, PM2.