Submissions for variant NM_000179.3(MSH6):c.457+2dup

dbSNP: rs876661224

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214122	SCV000279835	uncertain significance	not specified	2016-01-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 IVS2+2dupT or c.457+2dupT and consists of a duplication of one nucleotide at the +2 position in intron 2 of the MSH6 gene. The normal sequence with the bases that are duplicated in braces is CAGg{t}aaga. Multiple in silico models predict this variant to damage or destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. MSH6 c.457+2dupT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The nucleotide that is duplicated is conserved across species. Based on the currently available information, we consider MSH6 c.457+2dupT to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229584	SCV000551122	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-11-15	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234798). 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. 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.
Ambry Genetics	RCV002338697	SCV002636067	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	clinical testing	The c.457+2dupT intronic variant, results from a duplication of one nucleotide two nucleotides after coding exon 2 of the MSH6 gene. 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; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.