Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000479973 | SCV000566031 | uncertain significance | not provided | 2016-10-04 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.1633A>G at the cDNA level, p.Lys545Glu (K545E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been observed in at least one individual with endometrial cancer (Le Gallo 2012). MSH6 Lys545Glu 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 Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Lys545Glu occurs at a position that is conserved across species and is located in the MSH2 binding site and domain II of the MutS domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Lys545Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV000545794 | SCV000624670 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2023-12-16 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000574287 | SCV000662416 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-21 | criteria provided, single submitter | clinical testing | The p.K545E variant (also known as c.1633A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1633. The lysine at codon 545 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Center for Human Genetics, |
RCV000659891 | SCV000781788 | uncertain significance | Lynch syndrome 5 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000765683 | SCV000897025 | uncertain significance | Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000574287 | SCV000906723 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 545 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. The variant has been reported in an individual affected with endometrial cancer (PMID: 23104009). This variant has been identified in 1/251234 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. |
Baylor Genetics | RCV003470532 | SCV004195613 | uncertain significance | Endometrial carcinoma | 2023-08-04 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004002268 | SCV004841779 | uncertain significance | Lynch syndrome | 2023-10-30 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 545 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. The variant has been reported in an individual affected with endometrial cancer (PMID: 23104009). This variant has been identified in 1/251234 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. |