ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.660A>C (p.Glu220Asp)

gnomAD frequency: 0.00009  dbSNP: rs1800938
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075020 SCV000108241 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research MAF 1% in a specific population
GeneDx RCV000586585 SCV000149348 likely benign not provided 2020-11-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22495361, 16203774, 23621914, 15340264, 21153778, 10537275)
Invitae RCV001083284 SCV000153983 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115439 SCV000212886 likely benign Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200987 SCV000695924 likely benign not specified 2023-01-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.660A>C (p.Glu220Asp) 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. The variant allele was found at a frequency of 0.00014 in 249420 control chromosomes, predominantly at a frequency of 0.0002 within the South Asian subpopulation in the gnomAD database. This frequency is about 1.4-fold higher than the estimated maximal expected allele frequency of a pathogenic MSH6 variant. c.660A>C has been reported in the literature in individuals affected with cancer without evidence of cosegregation (Okkels_2012, Woods_2005, Li_2020, Muskens_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on MMR activity (Drost_2020). These results showed no damaging effect of this variant. Ten (other) submitters, including an expert panel, have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga) RCV000586585 SCV000702270 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115439 SCV000902751 benign Hereditary cancer-predisposing syndrome 2016-07-25 criteria provided, single submitter clinical testing
Mendelics RCV000986708 SCV001135793 likely benign Lynch syndrome 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586585 SCV001502306 likely benign not provided 2021-05-01 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000586585 SCV002010078 likely benign not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115439 SCV002536342 likely benign Hereditary cancer-predisposing syndrome 2021-03-29 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002498360 SCV002804571 likely benign Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3 2022-03-23 criteria provided, single submitter clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000986708 SCV004015986 likely benign Lynch syndrome 5 2023-07-07 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003421970 SCV004118176 uncertain significance MSH6-related condition 2023-08-03 criteria provided, single submitter clinical testing The MSH6 c.660A>C variant is predicted to result in the amino acid substitution p.Glu220Asp. This variant has been reported in both affected individuals and controls in the literature, and was interpreted as a polymorphism (Kolodner et al. 1999. PubMed ID: 10537275; Kim et al. 2004. PubMed ID: 15340264; Woods et al. 2005. PubMed ID: d) or an “unclassified” variant (Okkels et al. 2012. PubMed ID: 22495361; Terui et al. 2013. PubMed ID: 23621914). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48025782-A-C) and is interpreted as likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89551/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492404 SCV004239325 likely benign Breast and/or ovarian cancer 2023-06-29 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000200987 SCV000257305 uncertain significance not specified no assertion criteria provided research

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