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

gnomAD frequency: 0.00009  dbSNP: rs1800938

Total submissions: 18

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)
Labcorp Genetics (formerly Invitae), Labcorp	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: 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.
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	RCV004537284	SCV004118176	uncertain significance	MSH6-related disorder	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
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115439	SCV005045387	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200987	SCV005090473	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000200987	SCV000257305	uncertain significance	not specified		no assertion criteria provided	research