Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000163166 | SCV000213684 | likely benign | Hereditary cancer-predisposing syndrome | 2023-02-08 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Counsyl | RCV000409697 | SCV000487823 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2015-11-21 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000587335 | SCV000618186 | uncertain significance | not provided | 2024-05-01 | criteria provided, single submitter | clinical testing | In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23338612, 33471991, 22753075, 34359559, 29641532) |
Labcorp Genetics |
RCV000558825 | SCV000625186 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 228 of the MLH1 protein (p.Leu228Met). This variant is present in population databases (rs751628735, gnomAD 0.006%). 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: 184050). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
Color Diagnostics, |
RCV000163166 | SCV000684859 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-15 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with methionine at codon 228 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been reported in 9/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 7/282172 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587335 | SCV000696176 | uncertain significance | not provided | 2016-08-01 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.682C>A affects a non-conserved nucleotide and results in a replacement of a Leucine (L) with a Methionine (M). Both residues are medium size and hydrophobic, therefore this Leucine to Methionine substitution does not alter the physico-chemical properties of the protein. 3/4 in silico tools predict the variant to be disease causing. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0026% which does not exceed the maximal allele frequency of a disease causing MLH1 allele (0.07%) to exclude pathogenicity. To our knowledge, the variant has not been reported in affected patients from the literature and in vitro/vivo studies to assess the functional impact of the variant have not been published either. Clinical diagnostic centers classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Due to the lack of clinical and functional data, the variant was classified as a variant of uncertain significance until more information becomes available. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000587335 | SCV000889403 | uncertain significance | not provided | 2022-08-25 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000163166 | SCV002528772 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-16 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV000409697 | SCV004018099 | likely benign | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-03-13 | criteria provided, single submitter | clinical testing | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. |
Baylor Genetics | RCV000409697 | SCV004195080 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-11-18 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003995237 | SCV004840894 | uncertain significance | Lynch syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with methionine at codon 228 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 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 7/282172 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. |
Clinical Genetics Laboratory, |
RCV000587335 | SCV005199142 | uncertain significance | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000202192 | SCV000257114 | uncertain significance | not specified | no assertion criteria provided | research |