ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.3590_3593dup (p.Leu1200fs) (rs1553333738)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164350 SCV000214983 pathogenic Hereditary cancer-predisposing syndrome 2017-11-01 criteria provided, single submitter clinical testing ​The c.3980_3983dupATCA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of ATCA at position 3980 to 3983, causing a translational frameshift with a predicted alternate stop codon (p.L1330Vfs*12). This alteration was identified once from a pool of Scottish probands with either colon or endometrial cancer diagnosed before age 55 (Baglietto L et al. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000168228 SCV000218896 pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-04-05 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 9 of the MSH6 mRNA (c.3980_3983dupATCA), causing a frameshift at codon 1330. This creates a premature translational stop signal in the last exon of the MSH6 mRNA (p.Leu1330Valfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acids of the MSH6 protein. Loss-of-function variants in MSH6 are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with colorectal cancer or endometrial cancer (PMID: 20028993). A different variant (c.3984_3987dup), leading to the same protein effect (p.Leu1330Valfs*12), is a known Lynch syndrome founder mutation in the Ashkenazi Jewish population. This variant has been shown to abolish MSH6 expression and cause tumor microsatellite instability (PMID: 19851887). It has also been reported in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 24440087), and segregated with disease in a family affected with colorectal cancer (PMID: 14520694). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202005 SCV000568734 pathogenic not provided 2020-11-02 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Observed as homozygous in a patient with constitutional mismatch repair deficiency (CMMRD) (Toledano 2019); Observed as heterozygous in individuals with a personal or family history consistent with pathogenic variants in this gene (Baglietto 2010); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 31730237, 31501241, 20028993, 28152038, 31447099)
Color Health, Inc RCV000164350 SCV000905461 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826202 SCV000967756 pathogenic Lynch syndrome 2018-03-23 criteria provided, single submitter clinical testing The p.Leu1330fs variant in MSH6 has been reported in at least 1 individual with Lynch syndrome-associated cancers (Baglietto 2010). Additionally, another varian t at this position (c.3984_3987dupGTCA) leading to the same frameshift has been described as an Ashkenazi Jewish founder variant, and has been shown to cause lo ss of expression of MSH6 protein (Goldberg 2010). This variant has also been rep orted by other clinical laboratories in ClinVar (Variation ID 184998) and has be en identified in 1/109482 European chromosomes by gnomAD (http://gnomad.broadins titute.org). This variant is predicted to cause a frameshift, which alters the p rotein?s amino acid sequence beginning at position 1330 and leads to a premature termination codon 12 amino acids downstream. Although this termination codon oc curs within the last exon and is more likely to escape nonsense mediated decay ( NMD), the available evidence from the other Ashkenazi Jewish founder variant sho ws that the variant ultimately leads to loss of function. Heterozygous loss of f unction of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pat hogenic for Lynch syndrome in an autosomal dominant manner based upon the predic ted impact to the protein and the presence of an established pathogenic variant with the same amino acid change. ACMG/AMP Criteria applied: PS1; PVS1_Strong, PM 2.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000202005 SCV001250455 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420827 SCV001623216 pathogenic Hereditary nonpolyposis colon cancer 2021-05-01 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3980_3983dupATCA (p.Leu1330ValfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 246946 control chromosomes. c.3980_3983dupATCA has been reported in the literature in multiple individuals affected with Lynch syndrome and features of CMMRD (constitutional mismatch repair deficiency) (example, Baglietto_2010, Gardes_2012, Epsenschied_2017, Toledano_2019, Rootman_2020, Dong_2020). These data indicate that the variant is very 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. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202005 SCV000257290 likely pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358035 SCV001553672 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Leu1330ValfsX12 variant was identified in 3 of 69962 proband chromosomes (frequency: 0.00004) from individuals or families with lynch syndrome (Espenschied 2017). The variant was also identified in dbSNP (ID: rs786204180) as N/A, ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GenDxl; classified as likely pathogenic by Mayo Clinic), Clinvitae (classified as pathogenic by ClinVar and Invitae), databases. The variant was not identified in UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.3980_3983dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1330 and leads to a premature stop codon at position 1341. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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