ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1850A>C (p.Lys617Thr) (rs780199021)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196169 SCV000254360 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 617 of the MLH1 protein (p.Lys617Thr). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs780199021, ExAC 0.009%). This variant has been observed in an individual affected with clinical features of Lynch syndrome (PMID: 28449805). ClinVar contains an entry for this variant (Variation ID: 216334). 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 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.
Ambry Genetics RCV000234867 SCV000276966 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000234867 SCV000292195 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586570 SCV000696130 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1850A>C (p.Lys617Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 1/121402 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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