ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1508C>G (p.Ser503Cys) (rs63750897)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589037 SCV000604281 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115375 SCV000185775 benign Hereditary cancer-predisposing syndrome 2014-09-15 criteria provided, single submitter clinical testing
Color RCV000115375 SCV000537414 likely benign Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000078309 SCV000592587 likely benign not specified 2015-09-01 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000607345 SCV000734214 likely benign Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078309 SCV000110150 benign not specified 2013-10-29 criteria provided, single submitter clinical testing
GeneDx RCV000078309 SCV000149284 likely benign not specified 2018-03-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000607345 SCV000745650 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-04-21 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589037 SCV000695785 benign not provided 2017-01-26 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1508C>G (p.Ser503Cys) variant, located in the DNA mismatch repair protein MutS-like, N-terminal domain (via InterPro), causes a missense change involving a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools (SNPs&GO not captured due to low reliability index). The variant of interest was observed in the large and broad control population of ExAC with an allele frequency of 76/121318 (1/1596), predominantly in the European (Non-Finnish) cohort, 76/66712 (1/877), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. Multiple publications have cited the variant in affected individuals with HNPCC or HNPCC-related cancer with limited information (i.e. there is lack of co-occurrence and cosegregation information), although multiple authors have classified the variant as "benign" and reported presence of MSH6 protein expression in tumors of the CRC patients carrying this variant. In addition, a functional study (Drost_2011) reports the variant to have comparable MMR activity to that of wild-type. Furthermore, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign/benign. Therefore, the variant of interest has been classified as Benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074660 SCV000107862 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524113 SCV000166210 benign Hereditary nonpolyposis colon cancer 2018-01-22 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000078309 SCV000691927 benign not specified no assertion criteria provided clinical testing
Pathway Genomics RCV000172818 SCV000223784 likely benign Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
PreventionGenetics RCV000589037 SCV000805846 likely benign not provided 2017-06-21 criteria provided, single submitter clinical testing

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