ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)

dbSNP: rs1064793600
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Total submissions: 7
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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 The c.1618_1620delCTT variant (also known as p.L540del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame deletion of 3 nucleotides between positions 1618 and 1620. This results in the loss of a leucine at codon 540. This alteration has been identified in the germline of individuals whose Lynch-associated tumors displayed isolated loss of MSH6 on immunohistochemistry and/or high microsatellite instability (MSI-H). Furthermore, a second somatic pathogenic variant in MSH6 was also identified in these tumors (Ambry internal data). Based on an internal structural assessment, this alteration disrupts the structure of the connector 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) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-08-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000491419 SCV000822060 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV001543126 SCV001761645 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 5 2021-07-26 criteria provided, single submitter clinical testing The MSH6 c.1618_1620del (p.Leu540del) change is absent in gnomAD v2.1.1 (PM2_supporting; The change results in the deletion of a single leucine residue in the MSH2 binding region and MutS domain II (PM4). This variant has been reported as heterozygous in individuals with Lynch syndrome (PS4; PMID: 32635641, 30374176) and as homozygous in an individual with CMMRD (ClinVar Accession: SCV000813105.3). The colon and endometrial tumors of one individual carrying this germline alteration harbored unique second hits in MSH6 and microsatellite instability (PMID: 30374176). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria: PS4, PM2_supporting, PM4.

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