Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000167968 | SCV000218616 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 453 of the MLH1 protein (p.Lys453Asn). This variant is present in population databases (rs756099600, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, kidney cancer, ovarian cancer, and/or uterine cancer (PMID: 23047549, 29684080, 34326862). ClinVar contains an entry for this variant (Variation ID: 188113). 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 with a negative predictive value of 95%. 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. |
Ambry Genetics | RCV000214998 | SCV000273733 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-25 | criteria provided, single submitter | clinical testing | The p.K453N variant (also known as c.1359G>C), located in coding exon 12 of the MLH1 gene, results from a G to C substitution at nucleotide position 1359. The lysine at codon 453 is replaced by asparagine, an amino acid with similar properties. In one study, this variant was reported in 1/1893 women with epithelial ovarian cancer (Pal T et al. Br. J. Cancer. 2012 Nov; 107(10):1783-90). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590046 | SCV000696106 | uncertain significance | not provided | 2016-09-09 | criteria provided, single submitter | clinical testing | Variant summary: The MLH1 c.1359G>C (p.Lys453Asn) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 1/121006 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). This variant has been reported in one OvC patient without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more evidence becomes available. |
Color Diagnostics, |
RCV000214998 | SCV000910896 | likely benign | Hereditary cancer-predisposing syndrome | 2015-11-17 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000590046 | SCV002097443 | uncertain significance | not provided | 2023-04-19 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ovarian cancer (Pal et al., 2012); This variant is associated with the following publications: (PMID: 22753075, 23047549) |
Sema4, |
RCV000214998 | SCV002528642 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-08 | criteria provided, single submitter | curation |