ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.803A>G (p.Glu268Gly) (rs63750650)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075874 SCV000106889 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Ambry Genetics RCV000130956 SCV000185871 likely benign Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Intact protein function observed in appropriate functional assay(s)
Invitae RCV000524319 SCV000253146 benign not provided 2019-02-17 criteria provided, single submitter clinical testing
Counsyl RCV000410902 SCV000488222 benign Lynch syndrome II 2016-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000434087 SCV000513617 likely benign not specified 2018-02-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000434087 SCV000539639 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Insufficient evidence for pathogenicity, ExAC: 0.1% (6/6614) Finnish chromosomes
Color RCV000130956 SCV000684872 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000434087 SCV000919658 likely benign not specified 2017-12-08 criteria provided, single submitter clinical testing Variant summary: The c.803A>G (p.Glu268Gly) in MLH1 gene is a missense change that involves the alteration of a highly conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant is located within the DNA mismatch repair ATPase MutL domain, however displaying an MMR activity of 78.9% in one functional study (Takanashi_2001). This variant was found in 65/277352 control chromosomes (gnomAD) at a frequency of 0.0002344, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.001434 (37/25794). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. Liu_1998 reported a CRC with an alternate molecular basis for disease, where a pathogenic variant, MSH2 c.1552_1553delCA (p.Gln518Valfs), segregated with the disease, whereas MLH1 c.803A>G did not. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Benign/Likely Benign. Taking together, the variant was classified as Likely Benign.
CSER_CC_NCGL; University of Washington Medical Center RCV000148616 SCV000190331 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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