Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235804 | SCV000293282 | uncertain significance | not provided | 2017-11-16 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.335C>T at the cDNA level, p.Ser112Phe (S112F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. MSH2 Ser112Phe was not observed in large population cohorts (Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ser112Phe is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ser112Phe is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV001020082 | SCV001181513 | likely benign | Hereditary cancer-predisposing syndrome | 2022-03-04 | 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. |
| Labcorp Genetics |
RCV001211169 | SCV001382694 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-03-05 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 112 of the MSH2 protein (p.Ser112Phe). 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: 246010). 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 80%. 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. |
| Baylor Genetics | RCV004567776 | SCV005053478 | uncertain significance | Lynch syndrome 1 | 2024-01-24 | criteria provided, single submitter | clinical testing |