Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001025338 | SCV001187510 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-02-18 | criteria provided, single submitter | clinical testing | The p.D217Y variant (also known as c.649G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 649. The aspartic acid at codon 217 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration [also designated as c.648_649delAGinsTT if in cis with the MSH6 c.648A>T (p.T216T)] has been reported in a Portuguese patient with rectal cancer at age 45 years and was not observed in 108 control samples (Pinto C et al. Br. J. Cancer 2006 Sep;95:752-6). This amino acid position is not 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. |
All of Us Research Program, |
RCV004004660 | SCV004836741 | uncertain significance | Lynch syndrome | 2023-05-15 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with tyrosine at codon 217 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). 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 been reported in an individual affected with an early-onset colorectal cancer (PMID: 16940983). This variant has been identified in 3/247652 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. |