Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219365 | SCV000277229 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-07-17 | criteria provided, single submitter | clinical testing | The p.I257V variant (also known as c.769A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 769. The isoleucine at codon 257 is replaced by valine, 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 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is not well 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 p.I257V remains unclear. |
| Invitae | RCV000813096 | SCV000953434 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-06-13 | 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 232951). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with valine at codon 257 of the MLH1 protein (p.Ile257Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. |
| All of Us Research Program, |
RCV003998014 | SCV004839065 | uncertain significance | Lynch syndrome | 2024-01-08 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 257 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/251042 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. |