Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000524115 | SCV000166212 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-26 | criteria provided, single submitter | clinical testing | |
University of Washington Department of Laboratory Medicine, |
RCV000122952 | SCV000266202 | uncertain significance | Lynch syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000219239 | SCV000276977 | likely benign | Hereditary cancer-predisposing syndrome | 2023-11-18 | 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. |
Gene |
RCV000218729 | SCV000279307 | uncertain significance | not provided | 2022-02-23 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, colon, and other cancers (Maxwell 2016, Shirts 2016, Tung 2016); This variant is associated with the following publications: (PMID: 26976419, 23621914, 22949387, 26845104, 27153395, 17531815, 21120944) |
Counsyl | RCV000411179 | SCV000489645 | uncertain significance | Lynch syndrome 5 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000219239 | SCV000685206 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-08 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 533 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26845104, 26976419, 29684080), and in an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 4/251364 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, |
RCV000780476 | SCV000917757 | uncertain significance | not specified | 2018-04-13 | criteria provided, single submitter | clinical testing | Variant summary: MSH6 c.1599G>C (p.Glu533Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was observed with an allele frequency of 2e-05 in 246116 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (2e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.1599G>C, has been reported in the literature in individuals affected with Lynch Syndrome and Breast Cancer (Lu_2015, Shirts_2015, Tung_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance. |
Myriad Genetics, |
RCV000411179 | SCV004018982 | likely benign | Lynch syndrome 5 | 2023-03-29 | 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 | RCV003460868 | SCV004195581 | uncertain significance | Endometrial carcinoma | 2023-08-17 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000218729 | SCV004224911 | uncertain significance | not provided | 2022-04-27 | criteria provided, single submitter | clinical testing | BP4 |
CHEO Genetics Diagnostic Laboratory, |
RCV003492534 | SCV004239298 | uncertain significance | Breast and/or ovarian cancer | 2022-07-22 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV000122952 | SCV004839562 | uncertain significance | Lynch syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 533 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 individuals affected with breast cancer (PMID: 26845104, 26976419), and an individual affected cancer exhibiting microsatellite instability (PMID: 31391288). This variant has been identified in 4/251364 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. |