ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.918T>A (p.Asn306Lys) (rs587779054)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075934 SCV000106951 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000529157 SCV000625210 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-06-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 306 of the MLH1 protein (p.Asn306Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12011148; Leiden Open-source Variation Database (PMID: 21520333)). ClinVar contains an entry for this variant (Variation ID: 90441). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MLH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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