Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000206240 | SCV000259686 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-06-27 | criteria provided, single submitter | clinical testing | 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 of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 219679). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28726808). This variant is present in population databases (rs150478207, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 209 of the MLH1 protein (p.Asn209Thr). |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000507499 | SCV000601405 | uncertain significance | not specified | 2017-04-07 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001025057 | SCV001187179 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-09 | criteria provided, single submitter | clinical testing | The p.N209T variant (also known as c.626A>C), located in coding exon 8 of the MLH1 gene, results from an A to C substitution at nucleotide position 626. The asparagine at codon 209 is replaced by threonine, an amino acid with similar properties. This alteration has been identified 1/302 individuals with pancreatic cancer. (Chaffee KG et al. Genet Med, 2018 01;20:119-127). 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. |
Sema4, |
RCV001025057 | SCV002528761 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-21 | criteria provided, single submitter | curation | |
All of Us Research Program, |
RCV003997577 | SCV004835307 | uncertain significance | Lynch syndrome | 2023-09-17 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with threonine at codon 209 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 hereditary cancer in the literature. This variant has been identified in 1/251242 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. |