ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.116G>A (p.Cys39Tyr) (rs63751701)

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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) RCV000075134 SCV000106125 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
GeneDx RCV000202285 SCV000616778 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.116G>A at the cDNA level and p.Cys39Tyr (C39Y) at the protein level.It is located in the last nucleotide of exon 1 and results in the change of a Cysteine to a Tyrosine (TGT>TAT). MLH1c.116G>A (p.Cys39Tyr) has been observed in at least four individuals with colorectal cancer and one with endometrialcancer, three of whom are reported to meet either Amsterdam I or II Criteria (Scott 2001, Ward 2002, Steinke 2008,Coolbaugh-Murphy 2010, Hardt 2011, Telseth-Palmer 2016). Tumor testing is inconsistent with both microsatelliteinstability and microsatellite stability observed in tested colon tumors. Additionally, none of the tested colon tumors werereported to clearly show loss of the MLH1 protein via immunohistochemistry and results from MLH1 promoterhypermethylation studies were not provided (Ward 2002, Steinke 2008, Hardt 2011, Coolbaugh-Murphy 2010).Multiple splicing in silico models predict that MLH1 c.116G>A damages or destroys the natural splice donor site forintron 1 and leads to abnormal splicing. In addition, protein-based in silico analyses predict that MLH1 Cys39Tyr isprobably damaging to protein structure and function. However, in the absence of RNA or functional studies, the actualeffect of this variant is unknown. MLH1 c.116G>A (p.Cys39Tyr) was not observed in large population cohorts (NHLBIExome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Both the nucleotide, a guanine (G) atbase 166, and the amino acid, a Cysteine (C) at residue 39, are conserved across species. Although the InternationalSociety for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic, thisclassification appears to be primarily based on the predicted splicing impact given this variant’s position at the lastnucleotide of the exon (Thompson 2014). Based on current information, particularly the lack of convincing clinicalevidence supporting pathogenicity, we consider MLH1 c.116G>A (p.Cys39Tyr) to be a variant of uncertain significance.
Ambry Genetics RCV001010101 SCV001170249 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-27 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Last nucleotide of exon
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202285 SCV000257046 pathogenic not provided no assertion criteria provided research

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