ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2084C>A (p.Ser695Ter) (rs63749995)

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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) RCV000075523 SCV000106519 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Integrated Genetics/Laboratory Corporation of America RCV000075523 SCV000696144 likely pathogenic Lynch syndrome 2016-10-27 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2084C>A (p.Ser695X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.: p.Trp714X, p.His727fsX55). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120582 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV001059462 SCV001224086 pathogenic Hereditary nonpolyposis colon cancer 2019-02-06 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MLH1 gene (p.Ser695*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acids of the MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Lynch syndrome (PMID: 17505997). ClinVar contains an entry for this variant (Variation ID: 90038). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminus of the MLH1 protein. Other variant(s) that disrupt this region (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 24802709, 8797773, 27295708, 18566915, 18931482). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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