ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2561A>T (p.Lys854Met) (rs34374438)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129191 SCV000183929 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148652 SCV000190367 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585210 SCV000692987 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
Color RCV000129191 SCV000537549 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000121574 SCV000592609 uncertain significance not specified 2015-11-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764424 SCV000895481 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000585210 SCV000211298 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2561A>T at the cDNA level, p.Lys854Met (K854M) at the protein level, and results in the change of a Lysine to a Methionine (AAG>ATG). This variant has been observed in individuals with colon cancer, with at least two families fulfilling Bethesda Guidelines for Hereditary Non-polyposis Colorectal Cancer or Lynch syndrome, in two individuals with ovarian cancer, in an individual with familial breast cancer, and in one individual with thyroid cancer, but also in two healthy controls (Ohmiya 2001, Peterlongo 2003, Hampel 2005, Suchy 2006, Pal 2012, Bodian 2014, Yu 2015, Caminsky 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance based on insufficient evidence for classification (Thompson 2014). MSH6 Lys854Met was observed at an allele frequency of 0.24% (24/10,104) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Since Lysine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Lys854Met occurs at a position that is conserved across species and is located in the lever domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Lys854Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121574 SCV000085770 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000121574 SCV000695818 likely benign not specified 2019-05-09 criteria provided, single submitter clinical testing MSH6 c.2561A>T (p.Lys854Met) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 249996 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2561A>T has been reported in the literature in individuals affected with cancer including pancreatic cancer, Lynch Syndrome, ovarian cancer and prostate cancer (Isaacsson Velho_2018, Shindo_2017, Grant_2015, Pal_2012, Suchy_2006, Hampel_2005, Peterlongo_2003, Ohmiya_2001). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In one study examining non-medullary thyroid cancer, the variant of interest was detected in only one of the two affected individuals from a single family (Yu_2015). A co-occurrence with a pathogenic variant has been reported (BRCA2 c.1813delA, p.Ile605fsX9; internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) and once as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074754 SCV000107964 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524145 SCV000166221 likely benign Hereditary nonpolyposis colon cancer 2018-01-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000121574 SCV000539709 uncertain significance not specified 2016-06-23 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: ClinVar: 5 VUS (including expert panel, no evidence supporting pathogenicity since expert classification)
PreventionGenetics RCV000585210 SCV000805868 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000129191 SCV000805272 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing

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