Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000684903 | SCV000812364 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-06-16 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 141 of the MLH1 protein (p.Pro141Arg). This variant is present in population databases (rs746419577, gnomAD 0.0009%). 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: 565359). 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. 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 | RCV001022092 | SCV001183788 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-02-04 | criteria provided, single submitter | clinical testing | The p.P141R variant (also known as c.422C>G), located in coding exon 5 of the MLH1 gene, results from a C to G substitution at nucleotide position 422. The proline at codon 141 is replaced by arginine, an amino acid with dissimilar 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. |
All of Us Research Program, |
RCV004004224 | SCV004835283 | uncertain significance | Lynch syndrome | 2023-11-20 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with arginine at codon 141 of the MLH1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251432 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. |