ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1420C>G (p.Arg474Gly) (rs147939838)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115460 SCV000184512 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000115460 SCV000684743 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Counsyl RCV000412185 SCV000488993 uncertain significance Lynch syndrome II 2016-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000767186 SCV000149369 uncertain significance not provided 2016-08-19 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1420C>G at the cDNA level, p.Arg474Gly (R474G) at the protein level, and results in the change of an Arginine to a Glycine (CGG>GGG). This variant has been observed in at least one woman with early-onset breast cancer (Maxwell 2015). MLH1 Arg474Gly was observed with an allele frequency of 0.2% (7/4406) in African Americans in the NHLBI Exome Sequencing Project. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg474Gly occurs at a position that is conserved across species and is located in the region responsible for interaction with EXO1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg474Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200301 SCV000254348 likely benign Hereditary nonpolyposis colon cancer 2017-11-28 criteria provided, single submitter clinical testing
Mendelics RCV000708924 SCV000838017 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212537 SCV000601356 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing

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