Submissions for variant NM_000179.3(MSH6):c.1508C>G (p.Ser503Cys)

gnomAD frequency: 0.00059  dbSNP: rs63750897

Total submissions: 28

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
Eurofins Ntd Llc (ga)	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079925	SCV000166210	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115375	SCV000185775	benign	Hereditary cancer-predisposing syndrome	2014-09-15	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Pathway Genomics	RCV000172818	SCV000223784	likely benign	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115375	SCV000537414	benign	Hereditary cancer-predisposing syndrome	2022-01-01	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.
PreventionGenetics, part of Exact Sciences	RCV000589037	SCV000805846	likely benign	not provided	2017-06-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000607345	SCV001135805	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589037	SCV001152291	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MSH6: BP1, BS3:Supporting, BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589037	SCV002010117	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798251	SCV002042035	likely benign	Breast and/or ovarian cancer	2023-02-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078309	SCV002070928	likely benign	not specified	2021-11-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115375	SCV002535631	benign	Hereditary cancer-predisposing syndrome	2020-10-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000078309	SCV002552294	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498355	SCV002807885	likely benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-03-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115375	SCV002819239	likely benign	Hereditary cancer-predisposing syndrome	2022-11-22	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	Lynch syndrome 5		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000607345	SCV000745650	likely benign	Lynch syndrome 5	2016-04-21	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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589037	SCV001958064	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589037	SCV001975190	likely benign	not provided		no assertion criteria provided	clinical testing