Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589167 | SCV000696289 | likely pathogenic | Lynch syndrome | 2016-07-07 | criteria provided, single submitter | clinical testing | Variant summary: The MSH2 c.845_848delATGA (p.Asp282Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121262 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln718X, p.Val705fs), suggesting the variant to be pathogenic. In summary, the variant shows evidence for pathogenicity; it as a frameshift mutation and it is absent from controls. However, in the absence of clinical information about variant carriers and functional studies, the pathogenicity of the variant cannot be established with absolute certainty, therefore, this variant was classified as Likely Pathogenic. |
| Invitae | RCV001853978 | SCV002227887 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-05-05 | 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 create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 495774). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp282Valfs*9) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). |
| Ambry Genetics | RCV002448820 | SCV002680762 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-10-10 | criteria provided, single submitter | clinical testing | The c.845_848delATGA pathogenic mutation, located in coding exon 5 of the MSH2 gene, results from a deletion of 4 nucleotides at nucleotide positions 845 to 848, causing a translational frameshift with a predicted alternate stop codon. 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. |
| Baylor Genetics | RCV003465323 | SCV004196927 | likely pathogenic | Lynch syndrome 1 | 2021-11-09 | criteria provided, single submitter | clinical testing |