Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000586012 | SCV000211359 | likely benign | not provided | 2020-10-26 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10508506, 22102614, 22851212, 23621914, 24362816, 21120944, 24040339, 12019211, 26333163) |
Ambry Genetics | RCV000160725 | SCV000216588 | likely benign | Hereditary cancer-predisposing syndrome | 2019-04-09 | 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. |
Labcorp Genetics |
RCV000524164 | SCV000254311 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-24 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000586012 | SCV000601569 | uncertain significance | not provided | 2020-04-03 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000160725 | SCV000685377 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-27 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with arginine at codon 1087 of the MSH6 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). Functional studies have shown that this mutant protein has mismatch repair function, ability to bind with MSH2, and nuclear localization similar to wild type protein (PMID: 12019211, 22102614, 22851212, 24040339). This variant has been observed in individuals affected with colorectal and endometrial cancer (PMID: 10508506, 31307542), pancreatic cancer (PMID: 36230473), and breast and/or ovarian cancer (PMID: 34359559, 33471991). This variant has also been observed in healthy individuals (PMID: 34172528, 33471991). This variant has been identified in 14/282836 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, |
RCV000586012 | SCV000695852 | uncertain significance | not provided | 2016-03-07 | criteria provided, single submitter | clinical testing | Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Proline (P) with a large size and basic Arginine (R). 4/5 in silico tools predict the variant to be disease causing. The variant was observed in the Latino and Non-Finnish European subcohorts of the ExAC project at an allele frequency of 0.0064% which does not exceed the maximal expected allele frequency of a disease causing MSH6 allele (0.014%). The variant was reported in an HNPCC kindred that did not fulfill the Amsterdam criteria without strong evidence for pathogenicity (Kariola_HumMolGenet_2002). Independent functional studies assessing the variant for MMR proficiency, localization and impact on MSH6- MSH2 binding demonstrated no significance difference between WT MSH6 and MSH6 P1087R proteins (Belvederesi_FC_2012,Drost_MSH2_HM_2011, Kariola_HumMolGenet_2002, Wielders_PolsOne_2013). Clinical laboratories classify variant as Uncertain or Likely Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available. |
Mendelics | RCV000074829 | SCV000837912 | uncertain significance | Lynch syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000764430 | SCV000895487 | uncertain significance | Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000160725 | SCV002527998 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-11 | criteria provided, single submitter | curation | |
CHEO Genetics Diagnostic Laboratory, |
RCV003149721 | SCV003838324 | uncertain significance | Breast and/or ovarian cancer | 2022-03-24 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV000074829 | SCV004835031 | uncertain significance | Lynch syndrome | 2023-11-20 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with arginine at codon 1087 of the MSH6 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). Functional studies have shown that this mutant protein has mismatch repair function, ability to bind with MSH2, and nuclear localization similar to wild type protein (PMID: 12019211, 22102614, 22851212, 24040339). This variant has been observed in individuals affected with colorectal and endometrial cancer (PMID: 10508506, 31307542), pancreatic cancer (PMID: 36230473), and breast and/or ovarian cancer (PMID: 34359559, 33471991). This variant has also been observed in healthy individuals (PMID: 34172528, 33471991). This variant has been identified in 14/282836 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. |
Myriad Genetics, |
RCV004589547 | SCV005082030 | benign | Lynch syndrome 5 | 2024-04-04 | criteria provided, single submitter | clinical testing | This variant is considered 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: 27363726]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. |