Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000580288 | SCV000684779 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-29 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000629929 | SCV000750885 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-09-21 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 630 of the MLH1 protein (p.Ile630Met). This variant is present in population databases (rs774878438, gnomAD 0.007%). This missense change has been observed in individual(s) with rhabdosarcoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 489893). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781544 | SCV000919664 | uncertain significance | not specified | 2018-11-12 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.1890T>G (p.Ile630Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1890T>G, has been reported in the literature in individuals affected with Rhabdosarcoma (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV000580288 | SCV001174063 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-24 | criteria provided, single submitter | clinical testing | The p.I630M variant (also known as c.1890T>G), located in coding exon 16 of the MLH1 gene, results from a T to G substitution at nucleotide position 1890. The isoleucine at codon 630 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a rhabdosarcoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV004001250 | SCV004843230 | uncertain significance | Lynch syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing |