Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000558657 | SCV000624737 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-05-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). This variant has been observed in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 30013564). ClinVar contains an entry for this variant (Variation ID: 455182). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu747Serfs*9) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. |
Ambry Genetics | RCV002431514 | SCV002730969 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-02-08 | criteria provided, single submitter | clinical testing | The c.2238dupT variant, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 2238, causing a translational frameshift with a predicted alternate stop codon (p.L747Sfs*9). This mutation has been reported in conjunction with another MSH6 alteration in a patient who was diagnosed with medulloblastoma at age 6 and who was also found to have a cafe au lait macule (Tesch VK et al. Front Immunol, 2018 Jul;9:1506). 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. |
Myriad Genetics, |
RCV003449503 | SCV004185656 | pathogenic | Lynch syndrome 5 | 2023-08-16 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
All of Us Research Program, |
RCV004003673 | SCV004841323 | pathogenic | Lynch syndrome | 2023-10-23 | criteria provided, single submitter | clinical testing | This variant inserts 1 nucleotide in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with Constitutional mismatch repair deficiency who also carried the c.2980T>A, p.(Tyr994Asn) variant in MSH6 (PMID: 30013564). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |