Submissions for variant NM_000179.3(MSH6):c.4002-6_4002-1del

dbSNP: rs1670205307

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001178713	SCV001343225	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This c.4002-6_4002-1del variant causes a deletion of 6 nucleotides in intron 9 splice acceptor site of the MSH6 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although, to our knowledge, functional RNA studies have not been reported for this variant, it is expected to result in absent or non-functional gene product. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824926	SCV002074156	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-01-09	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4002-6_4002-1delTTTAAG is located in a canonical splice-site and is predicted to affect mRNA splicing. Several computational tools predict a significant impact on normal splicing: Four tools predict this variant will abolish the canonical 3' splice acceptor site and three tools predict the creation of a new 3' acceptor site which is shifted 5 nucleotides downstream (3'), creating a frameshift which may result in a significantly altered protein or creation of an premature termination codon. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 239160 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4002-6_4002-1delTTTAAG in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the literature. One ClinVar submitter has assessed this variant since 2014 where the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV002555491	SCV003218085	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	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. Variants that disrupt 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 disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 920134). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 9 of the MSH6 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.