ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1136A>T (p.Tyr379Phe) (rs143009528)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212530 SCV000149360 uncertain significance not provided 2014-08-04 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1136A>T at the cDNA level, p.Tyr379Phe (Y379F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign; however, a different missense variant at the same position, MLH1 Tyr379Cys has been reported in the literature also as a variant of uncertain significance. MLH1 Tyr379Phe 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 Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. MLH1 Tyr379Phe occurs at a position that is well conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MLH1 Tyr379Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115451 SCV000185286 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212530 SCV001134286 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing

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