ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1698T>A (p.Tyr566Ter)

dbSNP: rs876658915
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214834 SCV000279784 pathogenic not provided 2016-01-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1698T>A at the cDNA level and p.Tyr566Ter (Y566X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001854748 SCV002212861 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-12-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr566*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). 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 conditions. ClinVar contains an entry for this variant (Variation ID: 234763). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies.
Myriad Genetics, Inc. RCV003454679 SCV004186381 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-21 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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