ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1122T>G (p.Ser374Arg) (rs759868546)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206536 SCV000260121 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 374 of the MLH1 protein (p.Ser374Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs759868546, ExAC <0.01%) but has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 219943). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000411042 SCV000489201 uncertain significance Lynch syndrome II 2016-09-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001009894 SCV001170020 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-17 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001174565 SCV001337727 uncertain significance not specified 2020-01-03 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1122T>G (p.Ser374Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251436 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1122T>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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