Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002548511 | SCV003209561 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-05-30 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1049670). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12067992; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). |
| Myriad Genetics, |
RCV003449997 | SCV004189897 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-24 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. |
| KCCC/NGS Laboratory, |
RCV003449997 | SCV005201088 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2024-09-09 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 16 of the MLH1 gene.Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12067992; Invitae). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1049670). This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).. For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MLH1 gene cause Hereditary Non- Polyposis Colorectal Cancer Syndrome (HNPCC) also known as Lynch Syndrome. |
| Department of Pathology and Laboratory Medicine, |
RCV001356082 | SCV001551144 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The MLH1 c.1896+1G>C variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, or UMD-LSDB databases. However, we identified four families in the literature with variants at the same splice site (c.1896+1G>T, c.1896+1G>A, and c.1896+2T>C) all who met criteria for Lynch Syndrome (Wahlberg 2002, Mangold 2005, Lagerstedt-Robinson 2016). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The MLH1 c.1896+1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, GeneSplicer) predict a loss of the 5’ splice site. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |