Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076478 | SCV000107507 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Gene |
RCV000479442 | SCV000567757 | pathogenic | not provided | 2015-08-28 | criteria provided, single submitter | clinical testing | This pathogenic variant is denoted MSH2 c.2458+1G>A or IVS14+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 14 of the MSH2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual with a suggestive history of Lynch syndrome (Mangold 2005). we consider this variant to be pathogenic. |
| Ambry Genetics | RCV000491889 | SCV000580590 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-01-25 | criteria provided, single submitter | clinical testing | The c.2458+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the MSH2 gene. This mutation was previously identified in one individual whose personal and/or family history was suggestive of HNPCC (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702). This pathogenic mutation has also been identified in several families meeting Amsterdam criteria for HNPCC/Lynch syndrome with absent MSH2 staining on immunohistochemistry (IHC) (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000479442 | SCV000601466 | likely pathogenic | not provided | 2017-04-13 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000704889 | SCV000833861 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-02-28 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 14 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 15849733). ClinVar contains an entry for this variant (Variation ID: 90976). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). 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. |
| Color | RCV000491889 | SCV000908329 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-10-21 | criteria provided, single submitter | clinical testing |