Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| University of Washington Department of Laboratory Medicine, |
RCV000515776 | SCV000611872 | likely benign | Lynch syndrome | 2018-03-28 | criteria provided, single submitter | research | The MLH1 variant designated as NM_000249.3:c.836T>G (p.Val279Gly is classified as likely benign. The probability for this variant being pathogenic was 0.08% based on a PolyPhen-2 score of 0.99 and MAPP of 2.32 (Thompson et al. 2013, PMID: 22949379), so a pretest probability of 10% for Bayesian analysis was used for analysis. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of pathogenicity of 0.1608 to 1 (Thompson et al. 2003, PMID:12900794), providing additional evidence against pathogenicity. Additionally, this variant is a missense variant in a gene where truncating variants are pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives a 2% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MLH1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. |
| Invitae | RCV001344438 | SCV001538491 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-07-05 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 446501). This missense change has been observed in individual(s) with melanoma (PMID: 30374176). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 279 of the MLH1 protein (p.Val279Gly). |
| Ambry Genetics | RCV002438241 | SCV002677862 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-06-07 | criteria provided, single submitter | clinical testing | The p.V279G variant (also known as c.836T>G), located in coding exon 10 of the MLH1 gene, results from a T to G substitution at nucleotide position 836. The valine at codon 279 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with melanoma at age 61 who also had a family history of breast cancer in first and second degree relatives (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This amino acid position is highly 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, |
RCV000515776 | SCV004822007 | uncertain significance | Lynch syndrome | 2023-05-31 | criteria provided, single submitter | clinical testing |