Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002381221 | SCV002696483 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-11-06 | criteria provided, single submitter | clinical testing | The p.K461N variant (also known as c.1383G>C), located in coding exon 12 of the MLH1 gene, results from a G to C substitution at nucleotide position 1383. The lysine at codon 461 is replaced by asparagine, an amino acid with similar properties. This variant was classified as neutral by a classification algorithm reported in the literature (Ali H et al Hum. Mutat. 2012 Apr;33(4):642-50). 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, |
RCV004007310 | SCV004840999 | uncertain significance | Lynch syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with asparagine at codon 461 of the MLH1 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 MLH1-related disorders 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. |