Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000564188 | SCV000662076 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-08-03 | criteria provided, single submitter | clinical testing | The p.R18H variant (also known as c.53G>A), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 53. The arginine at codon 18 is replaced by histidine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001069605 | SCV001234784 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-11-08 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 479684). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 18 of the MLH1 protein (p.Arg18His). |
| Fulgent Genetics, |
RCV002483523 | SCV002775700 | uncertain significance | Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 | 2021-09-23 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004000841 | SCV004835224 | uncertain significance | Lynch syndrome | 2023-02-24 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with histidine at codon 18 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 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. |