Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076096 | SCV000107118 | uncertain significance | Lynch syndrome | 2018-10-18 | reviewed by expert panel | curation | Insufficient evidence: splicing not tested with RNA inhibitor |
| Ambry Genetics | RCV002444538 | SCV002682356 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-09-09 | criteria provided, single submitter | clinical testing | The c.1277-14C>G intronic variant results from a C to G substitution 14 nucleotides upstream from coding exon 8 in the MSH2 gene. This alteration was identified in an individual whose family history met Amsterdam II criteria for Lynch syndrome and small intestinal tumor demonstrated high microsatellite instability (MSI-H) with absent MSH2 and MSH6 staining on immunohistochemistry (IHC) (Ambry internal data). Furthermore, this alteration segregated with disease in five affected relatives of this family (Ambry internal data). This variant was also identified in a 44-year-old female whose family history met Amsterdam II criteria for Lynch syndrome and was diagnosed with MSI-high endometrial cancer with absent MSH2 staining on IHC and multiple sebaceous adenomas. Aberrant splicing was not observed upon RT-PCR analysis using patient RNA in this study; however, unstable aberrant splice products may have been undetected (Pagenstecher C et al Hum Genet. 2006 Mar;119(1-2):9-22). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This nucleotide position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to create an alternate splice acceptor site by the BDGP in silico model, but is only predicted to decrease the efficiency of the native splice acceptor site by the ESEfinder in silico model. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV002514348 | SCV003287705 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-03-26 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in activation of a cryptic slice site and skipping of exon 7 and introduces a premature termination codon (PMID: 31642931; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 90600). This variant has been observed in individuals with Lynch syndrome (PMID: 16341550; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |