ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2561A>T (p.Lys854Met) (rs34374438)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083699 SCV000166221 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129191 SCV000183929 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing The p.K854M variant (also known as c.2561A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 2561. The lysine at codon 854 is replaced by methionine, an amino acid with similar properties. This alteration was first described in the germline of an individual with an MSI-H colon tumor (Ohmiya N et al. Gene. 2001 Jul;272:301-13). The p.K854M alteration was also reported in a female diagnosed with ascending MSI-H colon cancer at age 76 whose tumor had absent MLH1, MSH6, and PMS2 staining, and it co-segregated with disease in a family with ovarian, intra-abdominal, and colorectal cancers (Hampel H et al. N. Engl. J. Med. 2005 May;352:1851-60; Suchy J et al. Clin. Genet. 2006 Jul;70:68-70; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90). However, this alteration has also been reported in individuals with tumor studies demonstrating MSS and intact IHC protein expression (Beroud C et al. Hum. Mutat. 2000;15:86-94 (Universal Mutation Database [available from]); Raskin L et al. Oncotarget. 2017 Jun 21;8:93450-93463). K854 is located in the MutS domain (domain III) and is adjacent to a conserved residue important for structural integrity, suggesting that the alteration may have a functional impact (Ohmiya N et al. Gene. 2001 Jul;272:301-13; Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000585210 SCV000211298 likely benign not provided 2021-03-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19389263, 14520694, 24728327, 16813607, 21153778, 23047549, 25637381, 15872200, 11470537, 26333163, 26898890, 25151137, 26530882, 23621914, 28767289, 29212164, 25479140, 29684080, 29368341, 28873162, 17531815)
Color Health, Inc RCV000129191 SCV000537549 likely benign Hereditary cancer-predisposing syndrome 2020-04-06 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)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585210 SCV000692987 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121574 SCV000695818 benign not specified 2021-06-06 criteria provided, single submitter clinical testing Variant summary: 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 Hereditary Nonpolyposis Colorectal Cancer 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). At-least one co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA2 c.1813delA, p.Ile605fsX9; internal testing), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a complete in vitro MMR (mismatch repair) activity (CIMRA) assay that was developed to quantify the functional activity of variants in MMR genes (Drost_2020). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the predominant evidence supporting a neutral outcome as outlined above, the variant was re-classified as benign.
PreventionGenetics,PreventionGenetics RCV000585210 SCV000805868 uncertain significance not provided 2017-07-06 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
Mendelics RCV000986723 SCV001135821 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000121574 SCV000085770 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148652 SCV000190367 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353909 SCV000592609 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Lys854Met variant was identified in 6 of 6608 proband chromosomes (frequency: 0.0009) from individuals with colorectal, prostate, pancreatic and ovarian cancer and was present in 1 of 168 control chromosomes (frequency: 0.006) from healthy individuals (Ohmiya 2001, Peterlongo 2003, Pal 2012, Shindo 2017, Grant 2015, Isaacson-Velho). The variant was identified in dbSNP (rs34374438) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by InSiGHT expert panel (2013), Ambry Genetics, GeneDx, and 8 other submitters and likely benign by Invitae and 1 other submitter) and UMD-LSDB (observed 1x). The variant was identified in control databases in 102 of 276,122 chromosomes at a frequency of 0.0004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 12 of 23,992 chromosomes (freq: 0.0005), Other in 2 of 6446 chromosomes (freq: 0.0003), Latino in 10 of 34,336 chromosomes (freq: 0.0003), European in 13 of 125,966 chromosomes (freq: 0.0001), Ashkenazi Jewish in 24 of 10,104 chromosomes (freq: 0.002), East Asian in 31 of 18,844 chromosomes (freq: 0.002), and South Asian in 10 of 30,740 chromosomes (freq: 0.0003); it was not observed in the Finnish population. This variant was identified by our laboratory with a co-occurring, pathogenic variant in MSH2 (c.1786_1788del, p.Asn596del) increasing the likelihood the c.2561A>T variant may not have clinical significance. The p.Lys854 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
True Health Diagnostics RCV000129191 SCV000805272 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093694 SCV001250878 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing

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