ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1621_1622delinsTT (p.Ala541Leu)

dbSNP: rs2084646294
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001062203 SCV001226985 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with leucine at codon 541 of the MLH1 protein (p.Ala541Leu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and leucine. 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. 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. This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency).
Ambry Genetics RCV002402439 SCV002705432 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-10 criteria provided, single submitter clinical testing The c.1621_1622delGCinsTT variant (also known as p.A541L), located in coding exon 14 of the MLH1 gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 1621 to 1622. This results in the substitution of the alanine residue for a leucine residue at codon 541, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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