ClinVar Miner

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

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078309 SCV000110150 benign not specified 2013-10-29 criteria provided, single submitter clinical testing
GeneDx RCV000589037 SCV000149284 likely benign not provided 2021-03-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22102614, 18566915, 18033691, 24113346, 27028851, 16010685, 20176959, 19924528, 23621914, 22495361, 15340264, 14871975, 18269114, 23047549, 10508506, 28608266, 27273229, 26483394, 22006311)
Invitae RCV001079925 SCV000166210 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115375 SCV000185775 benign Hereditary cancer-predisposing syndrome 2014-09-15 criteria provided, single submitter clinical testing This alteration is classified as 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.
Pathway Genomics RCV000172818 SCV000223784 likely benign Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115375 SCV000537414 likely benign Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589037 SCV000604281 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000607345 SCV000745650 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-04-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000589037 SCV000805846 likely benign not provided 2017-06-21 criteria provided, single submitter clinical testing
Mendelics RCV000607345 SCV001135805 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589037 SCV001152291 likely benign not provided 2019-05-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353430 SCV000592587 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Ser503Cys variant was identified in 12 of 9676 proband chromosomes (frequency: 0.0012) from Dutch, Korean, Scottish, and Danish individuals or families with hereditary and non-hereditary breast and colon cancer; the variant was present in 3 of 3752 control chromosomes (frequency: 0.001) from healthy individuals (Wijnen 1999, Kim 2004, Barneston 2008, Nilbert 2009, de Jong 2004). The variant was also identified in the following databases: dbSNP (ID: rs63750897) as “With other allele”, ClinVar (9x, as likely benign by Insight, GeneDx, Pathway Genomics, Color Genomics, COGR, ARUP, and Benign by EGL Genetic Diagnostics, Invitae and Ambry Genetics), Clinvitae (4x as likely benign and benign by ClinVar and EmvClass), COGR (as likely benign), UMD-LSDB (6 records, as neutral), Insight Colon Cancer Gene Variant Database (18x, as class 2), Mismatch Repair Genes Variant Database (5x), Insight Hereditary Tumors Database (18x, as likely benign). The variant was not identified in Cosmic, MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 178 of 276920 chromosomes at a frequency of 0.0006 in the following populations: African in 2 of 24028 chromosomes (freq. 0.00008), other in 2 of 6462 chromosomes (freq. 0.0003), Latino in 2 of 34386 chromosomes (freq. 0.00006), European non-Finnish in 171 of 126466 chromosomes (freq. 0.001), and European Finnish in 1 of 25790 chromosomes (freq. 0.00004), but was not seen in Ashkenazi Jewish, East Asian or South Asian populations (Genome Aggregation Consortium Feb 27, 2017). The p.Ser503Cys residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional studies on a yeast mutator assay using equivalent mutations at analogous chromosomal positions to assess mismatch repair (MMR) activity, found that the variant showed no significant difference between mutant and wildtype mutation rates (Martinez 2010). An additional functional assay measuring MMR mediated repair of a G-T mismatch engineered plasmid showed the variant to be MMR proficient (Drost 2012). The use of CoDP (Combination of different properties), a bioinformatics tool integrating prediction results of 3 in silico models and 2 structural properties, classified the variant as unlikely to be Lynch syndrome (or a carrier with a nonpathogenic variant), as it demonstrated MSS and showed normal expression of MSH6 (Terui 2013). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000078309 SCV000691927 benign not specified no assertion criteria provided 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
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000589037 SCV001798089 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000589037 SCV001918015 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000589037 SCV001932706 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000589037 SCV001958064 likely benign not provided no assertion criteria provided clinical testing

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