ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1667+4A>G (rs983986337)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464057 SCV000543585 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-10 criteria provided, single submitter clinical testing This sequence change falls in intron 14 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 not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 405403). 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.
Color Health, Inc RCV000777682 SCV000913613 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-26 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the +4 position of intron 14 of the MLH1 gene. To our knowledge, published RNA studies have not been reported for this variant to investigate its impact on splicing. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000777682 SCV001173103 likely benign Hereditary cancer-predisposing syndrome 2019-11-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);RNA Studies
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354080 SCV001548608 uncertain significance not provided no assertion criteria provided clinical testing The MLH1 c.1667+4A>G variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs983986337) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae and Color). 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.1667+4A>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. Further, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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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