Submissions for variant NM_000179.3(MSH6):c.3699_3702dup (p.Leu1235fs)

dbSNP: rs193922343

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491958	SCV000580141	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	The c.3699_3702dupAGAA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of AGAA at nucleotide position 3699, causing a translational frameshift with a predicted alternate stop codon (p.L1235Rfs*4). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694262	SCV000822698	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1235Argfs*4) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 24689082). ClinVar contains an entry for this variant (Variation ID: 218069). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781589	SCV000919755	likely pathogenic	Lynch syndrome	2018-08-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3699_3702dupAGAA (p.Leu1235ArgfsX4) 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. Another variant, affecting the same nucleotide positions, and leading to a similar protein level change, c.3699_3702delAGAA (p.Lys1233fsX6) and several other truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3799_3800delAT (p.Met1267fsX7), c.3840_3846delGGAGACT (p.Glu1281fsX44), c.3939_3940dupTC (p.Gln1314fsX14)). The variant was absent in 246004 control chromosomes (gnomAD). The variant, c.3699_3702dupAGAA, has been reported in the literature in an individual affected with colorectal cancer (Hansen 2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003454533	SCV004188244	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.
GeneDx	RCV000202173	SCV005333661	pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24689082)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005361165	SCV005919464	pathogenic	Mismatch repair cancer syndrome 3	2020-11-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202173	SCV000257274	likely pathogenic	not provided		no assertion criteria provided	research
Laboratory for Genotyping Development, RIKEN	RCV003165481	SCV002758250	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research