Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000576091 | SCV000676313 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-09-15 | criteria provided, single submitter | clinical testing | The p.E717D variant (also known as c.2151A>T), located in coding exon 19 of the MLH1 gene, results from an A to T substitution at nucleotide position 2151. The glutamic acid at codon 717 is replaced by aspartic acid, 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 T-cell ALL (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. |
| Labcorp Genetics |
RCV000630032 | SCV000750988 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 717 of the MLH1 protein (p.Glu717Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MLH1-related conditions (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 487010). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive 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. |
| Gene |
RCV001557751 | SCV001779568 | uncertain significance | not provided | 2023-06-27 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified as a germline variant in a pediatric patient with leukemia (Zhang et al., 2015); This variant is associated with the following publications: (PMID: 12799449, 20533529, 22753075, 26580448) |
| All of Us Research Program, |
RCV004001206 | SCV004843286 | uncertain significance | Lynch syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 717 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 been reported in individuals affected with T-cell acute lymphocytic leukemia (PMID: 26580448). This variant has not been identified 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. |