Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000479405 | SCV000567256 | uncertain significance | not provided | 2015-07-20 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.1830C>G at the cDNA level, p.His610Gln (H610Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAC>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 His610Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 His610Gln occurs at a position that is conserved in mammals and is located in the Lever domain and the region of interaction with EXO1 (Lutzen 2008, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 His610Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Color Diagnostics, |
RCV001186882 | SCV001353475 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-05 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with glutamine at codon 610 of the MSH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Labcorp Genetics |
RCV001851163 | SCV002136029 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 610 of the MSH2 protein (p.His610Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419452). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |