Submissions for variant NM_000179.3(MSH6):c.3814_3827dup (p.Asp1277fs)

dbSNP: rs1558393070

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000700703	SCV000829470	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1277Lysfs*55) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 577852). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 21155762, 24440087). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780486	SCV000917776	likely pathogenic	Lynch syndrome	2017-12-05	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3814_3827dupGAAAATGAATGTGA (p.Asp1277LysfsX55) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. c.3840_3846delGGAGACT (p.Glu1281fsX44), c.3938_3941dupTCCA (p.Gln1314fsX6), and c.3939_3957dupTCAAAAGGGACATAGAAAA (p.Ala1320fsX5)). This variant is absent in 245872 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985847	SCV001134444	pathogenic	not provided	2019-06-20	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV003279022	SCV004006244	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	The c.3814_3827dup14 variant, located in coding exon 9 of the MSH6 gene, results from a duplication of 14 nucleotides at positions 3814 to 3827, causing a translational frameshift with a predicted alternate stop codon (p.D1277Kfs*55). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 84 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003453485	SCV004185618	pathogenic	Lynch syndrome 5	2023-08-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.