ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.306G>A (p.Glu102=) (rs63751665)

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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) RCV000622520 SCV000740677 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation Criteria changed for variants in last base of exon therefore downgrade classification
Ambry Genetics RCV000215920 SCV000276776 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing Insufficient evidence;Last nucleotide of exon;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
GeneDx RCV000519380 SCV000618506 likely pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.306G>A at the DNA level. Although this variant is silent at the codinglevel, preserving a Glutamic Acid at codon 102, the variant occurs at the last nucleotide in the exon, and is predicted tocause abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant isunknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1c.306G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 GenomesConsortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 306, is conserved across species.Alternate changes at the same position, MLH1 c.306G>T and MLH1 c.306G>C, have been reported in individuals withcolorectal and/or endometrial cancer, have demonstrated skipping of exon 3 in RNA studies, and/or have exhibiteddeficient mismatch repair in in vitro studies (Takahashi 2007, Borras 2012, Buchanan 2014, Whitworth 2016). Basedon currently available information and internal clinical data, we consider MLH1 c.306G>A to be likely pathogenic.
Invitae RCV001241653 SCV001414684 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-17 criteria provided, single submitter clinical testing This sequence change affects codon 102 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. 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 present in population databases (rs63751665, ExAC 0.01%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 232603). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the c.306G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 26681312, 26659639, 21520333, 23729658, 17510385, 17576681, 9536098, 22736432). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. 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.

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