ClinVar Miner

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

gnomAD frequency: 0.00036  dbSNP: rs34374438
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Total submissions: 19
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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 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129191 SCV000183929 likely benign Hereditary cancer-predisposing syndrome 2020-10-21 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
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 Diagnostics, LLC DBA Color Health RCV000129191 SCV000537549 likely benign Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Center for Human Genetics 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, part of Exact Sciences RCV004528270 SCV000805868 uncertain significance MSH6-related disorder 2024-02-16 criteria provided, single submitter clinical testing The MSH6 c.2561A>T variant is predicted to result in the amino acid substitution p.Lys854Met. This variant has been reported in individuals with ovarian cancer (Pal et al. 2012, Table S1, PubMed ID: 23047549), colon cancer, melanoma (Ohmiya et al. 2001. PubMed ID: 11470537; Suchy et al. 2006. PubMed ID: 16813607), pancreatic cancer (Table S1, Shindo et al. 2017. PubMed ID: 28767289) and prostate cancer (Table S1, Isaacsson Velho et al. 2018. PubMed ID: 29368341), but in all cases was classified as a variant of uncertain significance. This variant was also identified in an individual from a cohort of healthy individuals (Table S1, Bodian et al. 2014. PubMed ID: 24728327) and has been reported with a frequency of 0.19% among individuals of Ashkenazi Jewish origin in the gnomAD database. In ClinVar, this variant has conflicting interpretations of pathogenicity including benign, likely benign, and uncertain ( At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics RCV000764424 SCV000895481 uncertain significance Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000986723 SCV001135821 benign Lynch syndrome 5 2023-08-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585210 SCV002046354 likely benign not provided 2022-10-21 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000129191 SCV002535751 likely benign Hereditary cancer-predisposing syndrome 2021-01-31 criteria provided, single submitter curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149719 SCV003838319 likely benign Breast and/or ovarian cancer 2022-03-11 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000129191 SCV004014954 benign Hereditary cancer-predisposing syndrome 2023-04-11 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 1 no assertion criteria provided clinical testing

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