ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.731G>A (p.Gly244Asp) (rs63750303)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573119 SCV000673849 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Integrated Genetics/Laboratory Corporation of America RCV000075830 SCV000919647 pathogenic Lynch syndrome 2017-09-21 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.731G>A (p.Gly244Asp) variant involves the alteration of a conserved nucleotide that results in a non-conservative amino acid substitution in the N-terminal part of the MLH1 protein which might be involved in protein interactions (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Published functional studies demonstrated that the variant protein virtually lost the ability to bind to its partner proteins (PMS2 or EXO1) and also resulted in a substantially decreased (19.4% of normal) in vitro MMR activity (Kondo 2003, Takahashi 2007). This variant is absent in 246120 control chromosomes. The variant was reported in multiple patients with colorectal cancer and other LS-associated tumors from Lynch syndrome families, including evidence of cosegregation with disease (e.g. Choi 2009, Bozzao 2011, Barrera 2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075830 SCV000106844 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.