Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000164768 | SCV000215444 | likely benign | Hereditary cancer-predisposing syndrome | 2022-04-27 | 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. |
Invitae | RCV000167935 | SCV000218583 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-12-29 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000486548 | SCV000566431 | uncertain significance | not provided | 2015-04-30 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.1484C>T at the cDNA level, p.Thr495Ile (T495I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr495Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr495Ile occurs at a position that is not conserved and is located within the clamp domain (Lutzen 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH2 Thr495Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Color Diagnostics, |
RCV000164768 | SCV001343690 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-26 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with isoleucine at codon 495 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a Lynch syndrome family, however, a pathogenic variant in MSH6 was also identified that could explain the observed phenotype (PMID: 27601186). This variant has been identified in 2/251298 chromosomes 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. |
All of Us Research Program, |
RCV003995363 | SCV004833452 | uncertain significance | Lynch syndrome | 2023-06-26 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with isoleucine at codon 495 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a Lynch syndrome family, however, a pathogenic variant in MSH6 was also identified that could explain the observed phenotype (PMID: 27601186). This variant has been identified in 2/251298 chromosomes 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. |