ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.306G>C (p.Glu102Asp) (rs63751665)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075636 SCV000106638 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causing splicing aberration predicted to interrupt known functional domains: full inactivation of variant allele
Invitae RCV001048439 SCV001212445 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 102 of the MLH1 protein (p.Glu102Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 3 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of Lynch syndrome (PMID: 22736432). ClinVar contains an entry for this variant (Variation ID: 90150). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22736432). This variant disrupts the p.Gly98 amino acid residue in MLH1. Other variant(s) that disrupt this residue has been determined to be pathogenic (PMID: 18772310, 21671081). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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