Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000567512 | SCV000669598 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-16 | criteria provided, single submitter | clinical testing | The p.H312P variant (also known as c.935A>C), located in coding exon 11 of the MLH1 gene, results from an A to C substitution at nucleotide position 935. The histidine at codon 312 is replaced by proline, 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. |
| Labcorp Genetics |
RCV001294308 | SCV001483180 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-04-02 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 312 of the MLH1 protein (p.His312Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 483576). 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. |
| Gene |
RCV003227796 | SCV003924810 | uncertain significance | not provided | 2022-11-09 | 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; Published functional studies demonstrate this variant is associated with normal splicing (Wai et al., 2020); This variant is associated with the following publications: (PMID: 22753075, 32123317) |