ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.790C>G (p.His264Asp) (rs63751597)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160528 SCV000211096 uncertain significance not provided 2015-09-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.790C>G at the cDNA level, p.His264Asp (H264D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAT>GAT). Although this variant has not been published in the literature as pathogenic or benign to our knowledge, two other missense variants in the same residue (His264Arg and His264Tyr) have been published in association with colorectal cancer, but are both classified as uncertain significance by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) based on conflicting functional assays (His264Arg), co-occurrence data (His264Tyr), and overall insufficient evidence for classification (Takahashi 2007, Chan 1999, Thompson 2014). MLH1 His264Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 His264Asp occurs at a position that is not conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 His264Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001089422 SCV000253144 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573493 SCV000669545 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-31 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000573493 SCV000689921 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030627 SCV001193609 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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