ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1327A>C (p.Lys443Gln) (rs34213726)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219360 SCV000274375 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-08 criteria provided, single submitter clinical testing Conflicting evidence
GeneDx RCV000235372 SCV000292610 likely benign not specified 2017-09-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000697163 SCV000825760 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 443 of the MLH1 protein (p.Lys443Gln). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs34213726, ExAC 0.001%). This variant has been reported in several individuals affected with colorectal cancer and gastric cancer (PMID: 15099349, 15872200, 16083711). ClinVar contains an entry for this variant (Variation ID: 89698). Experimental studies have shown that this missense change does not affect the expression, subcellular localization and interaction with PMS2, and exhibits an MMR activity similar to the wild-type protein, suggesting that this variant does not adversely affect protein function (PMID: 16083711, 20020535, 21136174, 22753075). 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 RCV000219360 SCV000906441 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144608 SCV000189935 uncertain significance Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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