Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235402 | SCV000293516 | uncertain significance | not provided | 2015-11-11 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.2009C>A at the cDNA level, p.Pro670His (P670H) at the protein level, and results in the change of a Proline to a Histidine (CCC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Pro670His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Pro670His occurs at a position that is conserved across species and is located in the ATPase domain and region of interaction with EXO1 (Lützen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Pro670His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000561699 | SCV000669809 | likely benign | Hereditary cancer-predisposing syndrome | 2022-01-19 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Mendelics | RCV000708838 | SCV000837845 | uncertain significance | Lynch syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001854866 | SCV002276965 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 670 of the MSH2 protein (p.Pro670His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 246114). 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. |