ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.1225_1227CTT[1] (p.Leu410del) (rs1064793600)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000515764 SCV000920456 pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability > 0.99 (0.992)
GeneDx RCV000481569 SCV000566567 uncertain significance not provided 2016-09-14 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in MSH6 is denoted c.1618_1620delCTT at the cDNA level and p.Leu540del (L540del) at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTT[CTT]AGCC. This deletion of a single Leucine residue occurs at a position that is conserved across species and is located in the MSH2 binding region and MutS domain II (Kariola 2002, Terui 2013). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. 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 Leu540del to be a variant of uncertain significance.
Ambry Genetics RCV000491419 SCV000580277 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
University of Washington Department of Laboratory Medicine, University of Washington RCV000515764 SCV000611879 pathogenic Lynch syndrome 2018-03-28 criteria provided, single submitter research The MSH6 variant designated as NM_000179.2:c.1618_1620del (p.Leu540del) is classified as pathogenic. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and gives a likelihood of 1.838 to 1, which supports pathogenicity (Thompson et al, 2003, PMID:12900794). In addition, endometrial and colorectal tumors from an affected individual in the family contained the germline MHS6 p.Leu540del variant. Each tumor had microsatellite instability and had a different independent second heterozygous pathogenic mutation in MSH6. Each of these observations supports classification of pathogenicity. In addition, this variant has previously been reported in two MSI high tumors with lack of MSH6 staining on IHC ( Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and increase cancer risk. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Invitae RCV000685620 SCV000813105 uncertain significance Hereditary nonpolyposis colon cancer 2018-05-17 criteria provided, single submitter clinical testing This variant, c.1618_1620delCTT, results in the deletion of 1 amino acid of the MSH6 protein (p.Leu540del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 419037). 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 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.
GeneKor MSA RCV000491419 SCV000822060 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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