ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1359G>C (p.Lys453Asn) (rs756099600)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167968 SCV000218616 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 453 of the MLH1 protein (p.Lys453Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs756099600, ExAC 0.001%). This variant has been reported in an individual with ovarian cancer (PMID: 23047549). It has also been observed in an individual with endometrial cancer in the Invitae database. However, in that individual a pathogenic allele was also identified in MSH6, which suggests that this c.1359G>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 188113). 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, 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 RCV000214998 SCV000273733 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000590046 SCV000696106 uncertain significance not provided 2016-09-09 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1359G>C (p.Lys453Asn) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 1/121006 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). This variant has been reported in one OvC patient without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more evidence becomes available.
Color RCV000214998 SCV000910896 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing

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