ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1243G>A (p.Asp415Asn) (rs373767220)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212533 SCV000211102 uncertain significance not provided 2018-12-14 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1243G>A at the cDNA level, p.Asp415Asn (D415N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant was observed in an individual with breast cancer (Tung 2015). MLH1 Asp415Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with EXO1 (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Asp415Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160532 SCV000217169 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000198513 SCV000254347 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 415 of the MLH1 protein (p.Asp415Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs373767220, ExAC 0.003%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 182524). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000515376 SCV000611397 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000160532 SCV000908626 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing

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