Total submissions: 6
| 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. |
| Invitae | RCV000694262 | SCV000822698 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-11-17 | 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, |
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, |
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. |
| Mayo Clinic Laboratories, |
RCV000202173 | SCV000257274 | likely pathogenic | not provided | no assertion criteria provided | research | ||
| Laboratory for Genotyping Development, |
RCV003165481 | SCV002758250 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |