ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3160A>T (p.Ile1054Phe) (rs267608075)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074806 SCV000108017 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
GeneDx RCV000586516 SCV000149312 likely benign not provided 2020-09-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23621914, 22645183, 22290698, 18301448, 23047549, 25479140)
Ambry Genetics RCV000115403 SCV000172809 likely benign Hereditary cancer-predisposing syndrome 2019-01-15 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV001080837 SCV000218996 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200988 SCV000695841 benign not specified 2021-07-16 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3160A>T (p.Ile1054Phe) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 246296 control chromosomes (gnomAD). The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), suggesting that the variant can be benign. c.3160A>T has been reported in the literature in an individual affected with colon cancer (Steinke_2008), however, the microsatellite status was stable in the associated tumor, and the MSH6 protein expression was preserved. The variant was reported in individuals with other tumor phenotypes (e.g. Pal_2012, Grant_2014, Dorling_2021), but was also found in several controls (Dorling_2021). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the relative repair efficiency of the p.I1054F variant protein was similar to the wild-type (Drost_2020). In addition, a recent multifactorial likelihood analysis that included allele frequency, co-occurrence, co-segregation, clinical and family history information as well as tumor characteristics, predicted this variant to be benign (Li_2020). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (n=2), likely benign (n=7) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000074806 SCV000837909 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586516 SCV000889484 likely benign not provided 2019-10-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115403 SCV000910609 benign Hereditary cancer-predisposing syndrome 2015-12-09 criteria provided, single submitter clinical testing
Mendelics RCV000986730 SCV001135831 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586516 SCV001152298 likely benign not provided 2016-05-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986730 SCV001302730 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262329 SCV001440153 likely benign Breast carcinoma 2019-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000586516 SCV000778622 likely benign not provided 2017-11-10 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074806 SCV001553951 likely benign Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Ile1054Phe variant was identified in 1 of 128 proband chromosomes (frequency: 0.008) from individuals or families with Lynch Syndrome (Steinke 2008). The variant was also identified in dbSNP (ID: rs267608075) as "With Uncertain significance allele ", ClinVar (classified as benign by Invitae; as likely benign by InSight, GeneDx, Mayo Clinic; as uncertain significance by Integrated Genetics/Laboratory Corporation of America), Cosmic (1x in breast tissue), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (1x). The variant was not identified in COGR, MutDB, UMD-LSDB, or Zhejiang University Database. The variant was identified in control databases in 46 of 272594 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 4 of 6410 chromosomes (freq: 0.0006), European in 18 of 125624 chromosomes (freq: 0.0001), Ashkenazi Jewish in 23 of 10110 chromosomes (freq: 0.002), and South Asian in 1 of 30758 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, East Asian, or Finnish populations. The p.Ile1054 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 addition, the variant demonstrated micro satellite stability and normal expression of MSH6 and prediction modeling determined the variant t be a polymorphism (Steinke 2008, 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.

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