Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000571492 | SCV000669556 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-28 | criteria provided, single submitter | clinical testing | The p.H315Y variant (also known as c.943C>T), located in coding exon 11 of the MLH1 gene, results from a C to T substitution at nucleotide position 943. The histidine at codon 315 is replaced by tyrosine, an amino acid with similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). 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. |
Color Diagnostics, |
RCV000571492 | SCV000689933 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-24 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with tyrosine at codon 315 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 been identified in 3/251402 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. |
Invitae | RCV001228581 | SCV001400986 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-06-16 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 483550). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs151119913, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 315 of the MLH1 protein (p.His315Tyr). |
Center for Genomic Medicine, |
RCV003493657 | SCV004243141 | uncertain significance | not specified | 2024-02-06 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004001027 | SCV004840927 | uncertain significance | Lynch syndrome | 2023-06-26 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with tyrosine at codon 315 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a general population control and absent in colorectal cancer or polyps cases (PMID: 30267214). This variant has been identified in 3/251402 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. |