Submissions for variant NM_000179.3(MSH6):c.3969_4001+52dup

dbSNP: rs1553333718

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204672	SCV000260127	uncertain significance	Lynch syndrome	2015-08-25	criteria provided, single submitter	clinical testing	This sequence change is a tandem duplication of 85 nucleotides in exon 9 of the MSH6 mRNA (c.3969_4001+52dup). This duplication includes the 3' end of exon 9. The impact of this duplication on both MSH6 mRNA processing and protein function is unknown. This variant is not present in population databases and has not been reported in the literature. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that while this duplication is not predicted to alter the consensus splice site in intron 9, it is predicted to create 2 novel splice sites downstream of the consensus splice site that if used, will create premature translation stop codon that resulting in a truncated MSH6 protein. In the absence of transcriptional studies, it is not known if these additional site actually impact MSH6 mRNA. In summary, this is a novel variant with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000771271	SCV000903402	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This variant creates an in-tandem duplication, encompassing the last 33 nucleotides of exon 9 and the first 52 nucleotides of intron 9 in the MSH6 gene. While this duplication does not directly disrupt the coding sequence of this gene, it creates a duplicate intron 9 splice donor site. To our knowledge, functional studies have not been reported for this variant. A similar duplication (c.3969_4001+51dup) has been reported in an individual affected with colorectal cancer whose tumor exhibited mismatch repair deficient characteristics (PMID: 14871975). 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	RCV000771271	SCV002623061	likely benign	Hereditary cancer-predisposing syndrome	2020-12-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV002517373	SCV002940988	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2015-08-25	criteria provided, single submitter	clinical testing	In summary, this is a novel variant with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that while this duplication is not predicted to alter the consensus splice site in intron 9, it is predicted to create 2 novel splice sites downstream of the consensus splice site that if used, will create premature translation stop codon that resulting in a truncated MSH6 protein. In the absence of transcriptional studies, it is not known if these additional site actually impact MSH6 mRNA. This variant is not present in population databases and has not been reported in the literature. This sequence change is a tandem duplication of 85 nucleotides in exon 9 of the MSH6 mRNA (c.3969_4001+52dup). This duplication includes the 3' end of exon 9. The impact of this duplication on both MSH6 mRNA processing and protein function is unknown.