Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000484112 | SCV000571205 | uncertain significance | not provided | 2016-08-01 | criteria provided, single submitter | clinical testing | This variant is denoted MSH2 c.746A>C at the cDNA level, p.Lys249Thr (K249T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys249Thr 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 Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Lys249Thr occurs at a position that is conserved across species and is located in the connector domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Lys249Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Ambry Genetics | RCV000566386 | SCV000664746 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-11 | criteria provided, single submitter | clinical testing | The p.K249T variant (also known as c.746A>C), located in coding exon 4 of the MSH2 gene, results from an A to C substitution at nucleotide position 746. The lysine at codon 249 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV001053129 | SCV001217375 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-08-25 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 421880). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 249 of the MSH2 protein (p.Lys249Thr). 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. 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. |
Color Diagnostics, |
RCV000566386 | SCV001345356 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-02-09 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with threonine at codon 249 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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. |
All of Us Research Program, |
RCV004003363 | SCV004829060 | uncertain significance | Lynch syndrome | 2023-07-13 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with threonine at codon 249 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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. |