Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV000583682 | SCV000690377 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-05-27 | criteria provided, single submitter | clinical testing | This variant deletes 1 nucleotide in exon 7 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000585938 | SCV000695875 | likely pathogenic | Hereditary nonpolyposis colon cancer | 2021-04-30 | criteria provided, single submitter | clinical testing | Variant summary: MSH6 c.3574delG (p.Val1192LeufsX3) 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 251366 control chromosomes. c.3574delG has been reported in the literature in at least one individual affected with Prostate Cancer (Isaacsson_2018). 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, |
RCV003139883 | SCV003806550 | pathogenic | Lynch syndrome 5 | 2023-01-12 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
Ambry Genetics | RCV000583682 | SCV004006209 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-22 | criteria provided, single submitter | clinical testing | The c.3574delG pathogenic mutation, located in coding exon 7 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3574, causing a translational frameshift with a predicted alternate stop codon (p.V1192Lfs*3). This alteration was seen in 1/150 unselected patients with recurrent or metastatic prostate cancer (Isaacsson Velho P et al. Prostate, 2018 Apr;78:401-407). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 | RCV003758867 | SCV004540317 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-09-03 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 491953). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 29368341). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val1192Leufs*3) 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). For these reasons, this variant has been classified as Pathogenic. |