Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000216742 | SCV000274941 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-24 | criteria provided, single submitter | clinical testing | The c.1705_1706delTT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides between positions 1705 and 1706, causing a translational frameshift with a predicted alternate stop codon (p.F569Hfs*7). This pathogenic mutation has been detected in an individual with colon cancer diagnosed at age 52 and a family history of endometrial cancer (Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81). 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. |
Labcorp Genetics |
RCV000542464 | SCV000624682 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-12-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Phe569Hisfs*7) 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 present in population databases (rs587783056, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 156507). For these reasons, this variant has been classified as Pathogenic. |
Color Diagnostics, |
RCV000216742 | SCV000905451 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-13 | criteria provided, single submitter | clinical testing | This variant deletes 2 nucleotides 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. To our knowledge, this variant has been reported in an individual referred for hereditary colorectal cancer screening (PMID: 28502729) and in an individual affected with colorectal cancer (PMID: 26023681). This variant has been identified in 1/31404 chromosomes 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, |
RCV000780461 | SCV000917728 | pathogenic | Lynch syndrome | 2018-12-28 | criteria provided, single submitter | clinical testing | Variant summary: The variant, MSH6 c.1705_1706delTT (p.Phe569HisfsX7) 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 (eg. c.1784delT (p.Leu595fsX15), c.2150_2153delTCAG (p.Val717fsX18)). The variant allele was found at a frequency of 3.2e-05 in 30970 control chromosomes. c.1705_1706delTT has been reported in the literature in an individual affected with colon cancer (Foley_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Human Genome Sequencing Center Clinical Lab, |
RCV001258039 | SCV001434867 | pathogenic | Lynch syndrome 5 | 2018-10-08 | criteria provided, single submitter | clinical testing | The c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is predicted to introduce a premature translation termination codon and is extremely rare in general population. Therefore, the c.1705_1706delTT (p.Phe569Hisfs*7) variant in the MSH6 gene is classified as pathogenic. |
Revvity Omics, |
RCV003137645 | SCV003822227 | pathogenic | not provided | 2022-05-20 | criteria provided, single submitter | clinical testing | |
Gene |
RCV003137645 | SCV003926442 | pathogenic | not provided | 2023-05-12 | 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; Observed in individual(s) with a personal or family history consistent with pathogenic variants in this gene (Foley et al., 2015); 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; This variant is associated with the following publications: (PMID: 24362816, 31447099, 18269114, 34594420, 32686686, 32832836, 26023681) |
Myriad Genetics, |
RCV001258039 | SCV004187407 | pathogenic | Lynch syndrome 5 | 2023-08-15 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
Baylor Genetics | RCV003462054 | SCV004195825 | pathogenic | Endometrial carcinoma | 2023-03-09 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV000780461 | SCV004837740 | pathogenic | Lynch syndrome | 2023-11-13 | criteria provided, single submitter | clinical testing | The c.1705_1706del (p.Phe569Hisfs*7) variant in the MSH6 gene is located on the exon 4 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Phe569Hisfs*7), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancers (PMID: 28514183, 23598716, 26023681, 31447099, 25479140, 30917047). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 156507). The variant is rare in the general population according to gnomAD (1/31404). Therefore, the c.1705_1706del (p.Phe569Hisfs*7) variant of MSH6 has been classified as pathogenic. |
Pathway Genomics | RCV000144627 | SCV000189954 | pathogenic | Lynch syndrome 1 | 2014-07-24 | no assertion criteria provided | clinical testing |