ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3980_3983dup (p.Leu1330fs) (rs1553333738)

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Total submissions: 6
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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 Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000164350 SCV000905461 pathogenic Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing
GeneDx RCV000202005 SCV000568734 pathogenic not provided 2017-11-09 criteria provided, single submitter clinical testing This duplication of four nucleotides in MSH6 is denoted c.3980_3983dupATCA at the cDNA level and p.Leu1330ValfsX12 (L1330VfsX12) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ATGA[dupATCA]GTCA. The duplication causes a frameshift which changes a Leucine to a Valine at codon 1330, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation as the last 31 amino acids are replaced with 11 incorrect amino acids. MSH6 c.3980_3983dupATCA has been observed in at least one individual with a personal history of colorectal or endometrial cancer (Baglietto 2010). In addition, an adjacent duplication event resulting in the same frameshift effect, MSH6 c.3984_3987dupGTCA, has been reported in association with Lynch syndrome and was observed in trans with another pathogenic MSH6 variant in at least one family with constitutional mismatch repair deficiency syndrome (Goldberg 2010, Raskin 2011, Bakry 2014). Based on currently available evidence, we consider MSH6 c.3980_3983dupATCA to be pathogenic.
Invitae RCV000168228 SCV000218896 pathogenic Hereditary nonpolyposis colon cancer 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.
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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202005 SCV000257290 likely pathogenic not provided no assertion criteria provided research

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