ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1421G>A (p.Arg474Gln) (rs63751083)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776166 SCV000911231 likely benign Hereditary cancer-predisposing syndrome 2016-08-06 criteria provided, single submitter clinical testing
Counsyl RCV000662517 SCV000785062 uncertain significance Lynch syndrome II 2017-03-29 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075211 SCV000106203 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000685340 SCV000812818 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 474 of the MLH1 protein (p.Arg474Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63751083, ExAC 0.001%). This variant has been reported in individuals affected with hereditary nonpolyposis colorectal cancer (PMID: 22736432, 18561205, 18383312). ClinVar contains an entry for this variant (Variation ID: 89737). In vitro and ex vivo experimental studies have shown that this missense change does not affect MLH1 mismatch repair activity, MLH1 protein expression, or RNA splicing (PMID: 22736432, 17510385, 18561205). 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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