Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001012134 | SCV001172555 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-15 | criteria provided, single submitter | clinical testing | The p.L521H variant (also known as c.1562T>A), located in coding exon 14 of the MLH1 gene, results from a T to A substitution at nucleotide position 1562. The leucine at codon 521 is replaced by histidine, an amino acid with similar properties. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193809 | SCV001362941 | uncertain significance | not specified | 2021-08-17 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.1562T>A (p.Leu521His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251184 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1562T>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has 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. |
| Invitae | RCV001860695 | SCV002196644 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 521 of the MLH1 protein (p.Leu521His). This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 819517). 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. |
| All of Us Research Program, |
RCV004004506 | SCV004841040 | uncertain significance | Lynch syndrome | 2023-02-24 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with histidine at codon 521 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 2/282582 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. |