ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.2647_2649AAG[1] (p.Lys884del) (rs267608073)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524151 SCV000261496 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-29 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 4 of the MSH6 mRNA (c.3040_3042delAAG). This leads to the deletion of 1 amino acid residue in the MSH6 protein (p.Lys1014del) but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals and families affected with Lynch syndrome associated tumors, including tumors with loss of MSH6 expression by immunohistochemistry and microsatellite instability (PMID: 12658575, 18301448, 26483394, Invitae). This variant is also known as 1013delCTT and c.3037_3039delAAG, p.Lys1013del in the literature. ClinVar contains an entry for this variant (Variation ID: 89333). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000409973 SCV000489395 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000759857 SCV000565230 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in MSH6 is denoted c.3040_3042delAAG at the cDNA level and p.Lys1014del (K1014del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAG[delAAG]TTGG. This variant, also reported as c.3037_3039delAAG, p.Lys1013del and 1013delTTC, has been observed in at least three individuals with a history of a Lynch syndrome related cancer; tumor testing on one of these individual?s colon tumor showed that it was MSI-H with loss of MSH2 and MSH6 via MMR IHC (Wagner 2003, Steinke 2008, Hu 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Lysine residue is located in the lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH6 Lys1014del to be a variant of uncertain significance.
Ambry Genetics RCV000491707 SCV000580309 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-24 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence;Other data supporting pathogenic classification
Color RCV000491707 SCV000690312 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759857 SCV000889479 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing

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