Submissions for variant NM_000179.3(MSH6):c.4001+1G>C

dbSNP: rs1114167729

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000490987	SCV000580199	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-31	criteria provided, single submitter	clinical testing	The c.4001+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 9 of the MSH6 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). This alteration occurs at the 3' terminus of the MSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 93 AA of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. 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 majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588908	SCV000695908	likely pathogenic	Lynch syndrome	2017-07-20	criteria provided, single submitter	clinical testing	Variant summary: The c.4001+1G>C (aka IVS9+1G>C) in a MSH6 gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to eliminate a canonical donor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from control datasets of ExAC and gnomAD (112936 and 270198 chrs tested, respectively). The variant has not, to our knowledge, been reported in affected individuals via publications, but is cited as Likely Pathogenic by a reputable database/clinical laboratory. In addition, two other alterations of the same nucleotide, c.4001+1G>A and c.4001+1G>T have been reported as casual in patients with CRC. Taken together, the variant was classified as Likely Pathogenic until additional information becomes available.
Myriad Genetics, Inc.	RCV003449309	SCV004189294	likely pathogenic	Lynch syndrome 5	2023-08-29	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.