Submissions for variant NM_000179.3(MSH6):c.1599G>C (p.Glu533Asp)

gnomAD frequency: 0.00001  dbSNP: rs373726731

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524115	SCV000166212	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-10-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	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.
GeneDx	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, LLC DBA Color Health	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, LabCorp	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, Inc.	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	2024-02-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000218729	SCV004224911	uncertain significance	not provided	2022-04-27	criteria provided, single submitter	clinical testing	BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492534	SCV004239298	uncertain significance	Breast and/or ovarian cancer	2022-07-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000411179	SCV005402204	uncertain significance	Lynch syndrome 5	2024-03-08	criteria provided, single submitter	clinical testing	The MSH6 c.1599G>C (p.Glu533Asp) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218729	SCV005626368	uncertain significance	not provided	2024-08-26	criteria provided, single submitter	clinical testing	The MSH6 c.1599G>C (p.Glu533Asp) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 29684080 (2018), 27153395 (2016), 26976419 (2016), 26845104 (2016), 26689913 (2015)), and in an individual with an unspecified cancer (PMID: 31391288 (2020)). The frequency of this variant in the general population, 0.000016 (4/251364 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.