ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3037AAG[1] (p.Lys1014del) (rs267608073)

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Total submissions: 7
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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 2020-06-30 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 2020-07-30 criteria provided, single submitter clinical testing The c.3040_3042delAAG variant (also known as p.K1014del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AAG deletion between nucleotide positions 3040 and 3042, resulting in the deletion of the amino acid lysine at codon 1014. This alteration has been identified in several individuals whose hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch associated tumors displayed high microsatellite instability (MSI-H) and/or isolated loss of MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This alteration has also been reported in individuals and families with HNPCC/Lynch associated cancers including one individual with pancreatic cancer (Hu C, et al. Cancer Epidemiol. Biomarkers Prev. 2015 Oct; Wagner A, et al. Am. J. Hum. Genet. 2003 May; 72(5):1088-100; Turner SA et al. Genet. Med., 2018 Jun). In addition, it was reported in a German individual who met Bethesda criteria and was diagnosed with MSI-H colorectal cancer at age 38 that displayed loss of both MSH2/MSH6 expression by IHC, but no mutations in MSH2 were detected (Steinke V et al. Eur. J. Hum. Genet., 2008 May;16:587-92). Of note, this alteration is also designated as 1013delCTT, c.3037_3039delAAG and p.Lys1013del in published literature. Based on an internal structural assessment, this alteration disrupts the fold of the lever domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals, but not in all available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc 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 2020-02-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290595 SCV001478684 likely pathogenic Hereditary nonpolyposis colon cancer 2021-01-09 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3040_3042delAAG (p.Lys1014del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 4.5e-06 in 220392 control chromosomes. c.3040_3042delAAG has been reported in the literature in comprehensively genotyped individuals affected with Lynch syndrome and associated tumors, supported by characteristic IHC and MSI findings (example, Wagner_2003, Steinke_2008, Hu_2016, Morak_2020, Turner_2019). These data indicate that the variant is likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic, n=2, VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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