ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1721T>C (p.Leu574Pro) (rs63751608)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075320 SCV000106314 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Abrogated function & co-segregation with disease
Invitae RCV000698457 SCV000827122 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 574 of the MLH1 protein (p.Leu574Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome-related cancers (PMID: 7757073, 15365995), and was shown to segregate with colon cancer in a family (PMID: 7757073). ClinVar contains an entry for this variant (Variation ID: 89846). This variant has been reported to affect MLH1 protein function (PMID: 21404117, 23403630, 9697702, 17510385, 10037723, 15864295, 12810663, 18094436, 11427529). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000075320 SCV000887320 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1721T>C has a 95.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

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