ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2060G>A (p.Arg687Gln) (rs587781310)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129035 SCV000172945 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Invitae RCV000168237 SCV000218906 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 687 of the MLH1 protein (p.Arg687Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587781310, ExAC 0.02%). This variant has been observed in an individual with a phenotype consistent with constitutional mismatch repair deficiency syndrome (CMMRD) (Invitae). However, that individual was also homozygous for a pathogenic variant in MSH6, which suggests that this c.2060G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 140838). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg687Trp) has been determined to be pathogenic (PMID: 11139242, 11748856, 14762794, 19697156, 21404117, 24440087, 26485756, 11920650, 17510385). This suggests that the Arg687 residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. 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.

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