ClinVar Miner

Submissions for variant NM_001354630.1(MLH1):c.1732-895_1732-893del (rs63750486)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075377 SCV000106372 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV000075377 SCV000543647 uncertain significance Lynch syndrome 2016-05-27 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 16 of the MLH1 mRNA (c.1835_1837delTTG). This leads to the deletion of 1 amino acid residue(s) in the MLH1 protein (p.Val612del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with suspected Lynch syndrome and in members of two unrelated Lynch syndrome families (PMID: 15849733, 16083711, 21404117). ClinVar contains an entry for this variant (Variation ID: 89900). Experimental studies have shown that this variant decreases expression of MLH1 protein and leads to reduced nuclear localization of PMS2 protein in vitro. However, the MMR activity was comparable to that of the wild-type protein (PMID: 16083711). In summary, this variant is an in-frame deletion of one amino acid residue that is absent from the population and reported in affected individuals, it has been shown to affect protein function in vitro. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000574309 SCV000673841 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Structural Evidence;Other data supporting pathogenic classification
Integrated Genetics/Laboratory Corporation of America RCV001193960 SCV001363156 likely pathogenic Lynch syndrome 2019-03-08 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1835_1837delTTG (p.Val612del) results in an in-frame deletion that is predicted to remove a valine from the encoded protein located in the C-terminal domain (IPR032189), which contains the region where MLH1 interacts with PMS2 (Raevaara 2005). The variant was absent in 277146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1835_1837delTTG has been reported in the literature in individuals affected with Lynch Syndrome, with at least one family that fulfilled the Amsterdam I criteria (Mangold 2005, Raevaara 2005, Hardt 2011), where the associated tumors demonstrated the loss of MLH1 expression (IHC) and increased microsatellite stability (Mangold 2005, Hardt 2011). A functional study demonstrated that the variant resulted in protein instability with considerably decreased MLH1 (and PMS2) quantities, and the variant MLH1 protein had about 76% relative repair activity, with somewhat reduced nuclear localization (Raevaara 2005). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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