ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2398G>C (p.Val800Leu)

gnomAD frequency: 0.00014  dbSNP: rs61748083
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680176 SCV000107953 likely benign Lynch syndrome 1 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
GeneDx RCV000656572 SCV000149298 likely benign not provided 2018-12-28 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.
Ambry Genetics RCV000115389 SCV000185791 likely benign Hereditary cancer-predisposing syndrome 2020-03-18 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.
Invitae RCV000524141 SCV000218910 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-31 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000074744 SCV000266206 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000409574 SCV000487846 uncertain significance Lynch syndrome 5 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000212665 SCV000539702 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3 papers, all describe as VUS/non-pathogenic; ExAC: 2/11540 Latino chromosomes
Preventiongenetics, part of Exact Sciences RCV000656572 SCV000805864 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115389 SCV000822062 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115389 SCV000902678 likely benign Hereditary cancer-predisposing syndrome 2015-12-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212665 SCV000917771 likely benign not specified 2023-02-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2398G>C (p.Val800Leu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of 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 9.2e-05 in 250774 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2398G>C has been reported in the literature in individuals affected with ovarian cancer (Pal_2012), renal cell carcinoma (Lu_2015), Breast Cancer (Wang_2018) and colorectal cancer (Kim_2004, Kolodner_1999, Shirts_2015), and in one report with positive segregation data, although the number of affected individuals in the family was not reported (Liccardo_2017). Some reports classified the variant as uncertain significance (example: Murphy_2022 and Tsaousis_2019). Co-occurrence with other pathogenic variant(s) have been reported (BRCA1 c.1252G>T, p.Glu418Ter), providing supporting evidence for a benign role for the variant (Wang_2018). At least one publication reports experimental evidence evaluating an impact on protein function. This variant had 91.8% activity in an in vitro MMR activity (CIMRA) assay supporting a benign role for this variant (Drost_2020). Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=12) and Likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000409574 SCV001135818 benign Lynch syndrome 5 2023-08-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212665 SCV001158690 uncertain significance not specified 2019-05-07 criteria provided, single submitter clinical testing The MSH6 c.2398G>C; p.Val800Leu variant (rs61748083) is reported in the literature in individuals with colorectal cancer or ovarian cancer (Kim 2004, Kolodner 1999, Pal 2012, Shirts 2016), but is also reported in a healthy control (Kolodner 1999). This variant is reported in ClinVar (Variation ID: 89279). It is found in the general population with an overall allele frequency of 0.009% (26/282172 alleles) in the Genome Aggregation Database. The valine at codon 800 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Kim JC et al. Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer. 2004;3(2):129-37. Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999 Oct 15;59(20):5068-74. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000074744 SCV001450733 uncertain significance Lynch syndrome 2020-10-19 criteria provided, single submitter clinical testing The MSH6 c.2398G>C (p.Val800Leu) missense change has a maximum subpopulation frequency of 0.017% in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48027520-G-C). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 26845104, 28481244, 10537275). In case control studies, this variant was identified in one control participant and no colorectal cancer patients (PMID: 30267214), while in another case control study the variant was identified at a similar frequency in colorectal cancer cases and normal controls (PMID: 10537275). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000656572 SCV002010104 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798252 SCV002042041 uncertain significance Breast and/or ovarian cancer 2021-04-20 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115389 SCV002535732 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-16 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000409574 SCV004018995 benign Lynch syndrome 5 2023-03-29 criteria provided, single submitter clinical testing This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CSER _CC_NCGL, University of Washington RCV000148650 SCV000190365 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353412 SCV000592608 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Val800Leu variant was identified in 1 of 558 proband chromosomes (frequency 0.002) from individuals with colorectal cancer (Kim 2004, Kolodner 1999) and was identified in 1 of 1038 control chromosomes (frequency 0.001) from these studies, increasing the likelihood that this may be a low frequency polymorphism. This variant was also identified in dbSNP (ID# rs61748083) “with untested allele”, in the Exome Variant Server ESP Project with a frequency of 0.0002 in European American alleles, and in the HGMD, MutDB, MMR DB, and InSIGHT Colon Cancer databases. The p.Val800 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. In addition, two in silico studies which assessed the impact of the variant on protein structure and function predicted this variant was neutral (Ali 2012, Terui 2013). However, this information is not predictive enough to rule out pathogenicity. 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 predicted benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656572 SCV000778620 uncertain significance not provided 2018-02-20 no assertion criteria provided clinical testing

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