Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491971 | SCV000580304 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-05-20 | criteria provided, single submitter | clinical testing | The p.D390E variant (also known as c.1170T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 1170. The aspartic acid at codon 390 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.006 (Terui H et al. J. Biomed. Sci. 2013;20:25). Since supporting evidence is limited at this time, the clinical significance of p.D390E remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001805109 | SCV002051066 | uncertain significance | not specified | 2021-12-12 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002523981 | SCV003499977 | benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-24 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004003461 | SCV004843081 | uncertain significance | Lynch syndrome | 2024-01-08 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 390 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 5/251040 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. |