ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.884+3A>G (rs267607803)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221867 SCV000273706 pathogenic Hereditary cancer-predisposing syndrome 2019-02-03 criteria provided, single submitter clinical testing The c.884+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 10 in the MLH1 gene. This alteration has been reported in one family that met clinical criteria for HNPCC where the proband's tumor showed high microsatellite instability and the loss of MLH1 staining on IHC (Terdiman JP et al. Gastroenterology. 2001 Jan;120:21-30). This variant was observed to segregate with colon and uterine cancer in many members of one family (Ambry internal data). RNA analysis from multiple carriers from two families reflects a significant increase in exon 10 and exon 10 + 11 skipping, both of which are predicted to result in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay (Ambry internal data). Several other alterations at this splice donor site have also been shown to induce exon 10 skipping (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Casey G et al. JAMA. 2005 Feb;293:799-809; Rahner N et al. Acta Oncol. 2007;46:763-9; Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24; Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Soukarieh O et al. PLoS Genet. 2016 Jan;12:e1005756; Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Spaepen M et al. Fam. Cancer. 2006;5:179-89). Based on the majority of available evidence, this alteration is classified as a disease-causing mutation.
Invitae RCV000629748 SCV000750704 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-11-29 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 11208710). ClinVar contains an entry for this variant (Variation ID: 90413). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000663124 SCV000786258 likely pathogenic Lynch syndrome II 2018-03-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985790 SCV001134325 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000985790 SCV001550149 uncertain significance not provided no assertion criteria provided clinical testing The MLH1 c.884+3A>G variant was identified in 1 of 218 proband chromosomes (frequency: 0.005) from individuals or families with HNPCC (Terdiman 2001). The variant was also identified in dbSNP (ID: rs267607803) as “With Pathogenic allele”, ClinVar (classified as uncertain significance by InSight and Invitae; as likely pathogenic by Counsyl; and as pathogenic by Ambry Genetics), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors database (2x). The variant was not identified in GeneInsight-COGR, UMD-LSDB, or Zhejiang University databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.884+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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