ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2210A>T (p.Asp737Val) (rs267607885)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115474 SCV000149383 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2210A>T at the cDNA level, p.Asp737Val (D737V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant was observed in the germline of an individual with colon cancer whose family history fulfilled Amsterdam Criteria for Lynch syndrome or Hereditary Nonpolyposis Colorectal Cancer (HNPCC). However, this variant co-occurred in trans with a pathogenic MLH1 mutation in this individual, and was reported to not segregate with disease in the family (Mangold 2005, Pagenstecher 2006). This variant has also been observed in the colon tumor of a patient with HNPCC and a germline MLH1 nonsense variant (Nakahara 1997). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance based on insufficient evidence (Thompson 2014). MLH1 Asp737Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the PMS2/MLH3/PMS1 interaction region (Raevaara 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Asp737Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000791373 SCV000254367 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 737 of the MLH1 protein (p.Asp737Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with colorectal cancer (PMID: 16341550). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2210A>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 90090). 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. 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.
Ambry Genetics RCV000563079 SCV000662010 likely benign Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Co-occurence with mutation in same gene (phase unknown),Does not segregate with disease in family study (genes with incomplete penetrance)
Color RCV000563079 SCV000684805 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing

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