Submissions for variant NM_000179.3(MSH6):c.900dup (p.Lys301fs)

dbSNP: rs863225421

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213447	SCV000276263	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The c.900dupG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of G at nucleotide position 900, causing a translational frameshift with a predicted alternate stop codon (p.K301Efs*11). This mutation has been reported in a Norwegian family with Lynch syndrome (Sjursen W et al. J. Med. Genet. 2010 Sep; 47(9):579-85). It was also identified in 1/369 Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000629753	SCV000750709	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 218080). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20587412, 27601186). This sequence change creates a premature translational stop signal (p.Lys301Glufs*11) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825624	SCV000966978	pathogenic	Lynch syndrome	2018-10-17	criteria provided, single submitter	clinical testing	The p.Lys301GlufsX11 variant in MSH6 has been reported in 3 individuals with cli nical features of Lynch syndrome and segregated with disease in at least 1 affec ted relative from 1 family (Sjursen 2010, Lagerstedt-Robinson 2016, DeRycke 2017 ). In this family, tumors sampled from individuals exhibited a loss of MSH6 and MSH2 expression by immunohistochemistry (Sjursen 2010). This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID 218080) and was absent from large population studies. The p.Lys301GlufsX11 variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 301 and leads to a premature termination codon 11 amino acids do wnstream. This alteration is then predicted to lead to a truncated or absent pro tein. Loss of function of the MSH6 gene is an established disease mechanism in L ynch syndrome. In summary, this variant meets criteria to be classified as patho genic for Lynch syndrome in an autosomal dominant manner, based upon predicted i mpact to the protein, absence from the general population, functional evidence f rom an established function study and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS3, PS4_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825624	SCV001338297	pathogenic	Lynch syndrome	2020-02-13	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.900dupG (p.Lys301GlufsX11) 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 was absent in 251284 control chromosomes (gnomAD). c.900dupG has been reported in the literature in individuals affected with Lynch syndrome and CRC (Sjursen_2010, Lagerstedt-Robinson_2016, DeRycke_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202094	SCV001450097	pathogenic	not provided	2014-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454535	SCV004188273	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202094	SCV000257308	pathogenic	not provided		no assertion criteria provided	research