ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1853A>T (p.Lys618Met) (rs63750449)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220697 SCV000273717 uncertain significance Hereditary cancer-predisposing syndrome 2015-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000220697 SCV000689844 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Counsyl RCV000662568 SCV000785173 uncertain significance Lynch syndrome II 2017-05-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503018 SCV000592426 uncertain significance not specified 2016-12-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588543 SCV000696131 uncertain significance not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.1853A>T variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a pathogenic outcome (SNPs&GO not captured here due to low reliability index). The variant is absent from the large, broad ExAC control population. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One reputable clinical lab has classified the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS), until additional information becomes available.
Invitae RCV000168095 SCV000218751 uncertain significance Hereditary nonpolyposis colon cancer 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces lysine with methionine at codon 618 of the MLH1 protein (p.Lys618Met). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 188186). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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