Submissions for variant NM_000179.3(MSH6):c.3936_4001+8dup

dbSNP: rs1572747475

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000820841	SCV000961572	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-01-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001185050	SCV001351180	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This variant results in the duplication of 74 nucleotides including the last 66 nucleotides of exon 9 and first 8 nucleotides of intron 9 of the MSH6 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 36612224). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001185050	SCV002626122	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The c.3936_4001+8dup74 variant spans the canonical donor site of coding exon 9 in the MSH6 gene. This variant results from a duplication of 74 nucleotides at positions c.3936 to c.4001+8. The canonical donor site is highly conserved on limited sequence alignment. In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004002825	SCV004829592	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This variant results in the duplication of 74 nucleotides including the last 66 nucleotides of exon 9 and first 8 nucleotides of intron 9 of the MSH6 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 36612224). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.