Submissions for variant NM_000179.3(MSH6):c.3801+1del

dbSNP: rs1553333185

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536924	SCV000624921	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2017-06-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 21388660). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). 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. This sequence change affects a donor splice site in intron 8 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002367766	SCV002625432	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-05-02	criteria provided, single submitter	clinical testing	The c.3801+1delG intronic variant, located in intron 8 of the MSH6 gene, results from a deletion of the first nucleotide within intron 8 of the MSH6 gene. This alteration has been identified in an ovarian cancer patient and in 1/369 Swedish Lynch syndrome families (Ketabi Z et al. Gynecol Oncol. 2011 Jun 1;121(3):462-5; Lagerstedt-Robinson K et al. Oncol Rep. 2016 Nov;36(5):2823-2835). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, the strength of the native donor splice site is maintained, but shifted upstream one nucleotide resulting in a translational frameshift with a predicted alternate stop codon (p.A1268Hfs*4); however, direct evidence is unavailable. This alteration is predicted to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003449513	SCV004189277	likely pathogenic	Lynch syndrome 5	2023-08-25	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.