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
Counsyl RCV000662517 SCV000785062 uncertain significance Lynch syndrome II 2017-03-29 criteria provided, single submitter clinical testing
Invitae RCV000685340 SCV000812818 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-18 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 Lynch syndrome (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, 30998989). 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.
Color Health, Inc RCV000776166 SCV000911231 likely benign Hereditary cancer-predisposing syndrome 2016-08-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000776166 SCV001171839 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-15 criteria provided, single submitter clinical testing The p.R474Q variant (also known as c.1421G>A), located in coding exon 13 of the MLH1 gene, results from a G to A substitution at nucleotide position 1421. The arginine at codon 474 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in one individual either fulfilling Amsterdam II criteria or with a family history suspicious for Lynch syndrome and with a tumor demonstrating microsatellite instability (Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24). An in vitro functional study showed that p.R474Q had ATPase activity similar to wild-type MLH1 (Räschle M et al. J. Biol. Chem. 2002 Jun;277:21810-20). Another yeast-based functional assay showed that this alteration retained 81.1% of mismatch repair activity compared to wild-type and also showed greater than 75% relative MLH1 protein expression compared to wild-type (Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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