Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001013324 | SCV001173899 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-16 | criteria provided, single submitter | clinical testing | The p.I611T variant (also known as c.1832T>C), located in coding exon 16 of the MLH1 gene, results from a T to C substitution at nucleotide position 1832. The isoleucine at codon 611 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a cohort of patients with pancreatic ductal adenocarcinoma (PDAC) unselected for family history (Hu C et al. Cancer Epidemiol. Biomarkers Prev., 2016 Jan;25:207-11). 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. |
| Invitae | RCV001299004 | SCV001488080 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-07-25 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 611 of the MLH1 protein (p.Ile611Thr). This variant is present in population databases (rs141688321, gnomAD 0.007%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 26483394). ClinVar contains an entry for this variant (Variation ID: 820147). 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. |