ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4022_4077dup (p.Leu1360delinsLysGlyGlnLeuTer) (rs1553334006)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485302 SCV000569459 uncertain significance not provided 2016-02-25 criteria provided, single submitter clinical testing This duplication of 56 nucleotides in MSH6 is denoted c.4022_4077dup56 at the cDNA level and p.Leu1360LysfsX5 (p.L1360KfsX5) at the protein level. The normal sequence is AGTG[dup56]TTAT. The duplication causes a frameshift, which changes a Leucine to a Lysine at codon 1360, the last residue of the MSH6 gene, and results in an extension of the protein by five amino acids. This variant occurs in the C-terminal region of MSH6, which is a binding site for MSH2 (Kariola 2002). MSH6 c.4022_4077dup56 has not, to our knowledge, been reported in the literature. Based on currently available information, it is unclear whether MSH6 c.4022_4077dup56 is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572669 SCV000662484 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing Insufficient evidence;Gross duplications without strong evidence for pathogenic or benign
Invitae RCV000703204 SCV000832092 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-03-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Leu1360Lysfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last amino of the MSH6 protein and extend the length of the protein by three additional amino acids. 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 disease. ClinVar contains an entry for this variant (Variation ID: 420575). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acid is currently unknown. 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.
Mendelics RCV000708899 SCV000837936 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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