ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.125C>T (p.Ala42Val) (rs587778901)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212513 SCV000149364 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.125C>T at the cDNA level or p.Ala42Val (A42V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has been previously reported in the literature with conflicting evidence on pathogenicity. Ellison et al. (2004) demonstrated significant loss of mismatch repair activity in association with this variant in a hybrid human-yeast assay. Walsh et al. (2011) identified MLH1 Ala42Val in 1/360 women with ovarian, fallopian tube, or peritoneal carcinoma, and concluded that it is benign based on the fact that tumor testing did not exhibit high microsatellite instability or loss of mismatch repair protein expression. MLH1 Ala42Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ala42Val occurs at a position that is conserved across species, and is located in the ATP-binding and hydrolysis domains within the N-terminal ATPase domain (Raevaara 2005, Kansikas 2011, Andersen 2012) . In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ala42Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115455 SCV000216707 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);Insufficient evidence
Invitae RCV000524229 SCV000284012 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 42 of the MLH1 protein (p.Ala42Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (rs587778901, ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 22006311). ClinVar contains an entry for this variant (Variation ID: 89688). Experimental studies in yeast have shown that this missense change disrupts MLH1 mismatch repair activity (PMID: 15475387). 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.
Counsyl RCV000411578 SCV000489084 uncertain significance Lynch syndrome II 2016-08-16 criteria provided, single submitter clinical testing
Color RCV000115455 SCV000684733 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212513 SCV000805946 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212513 SCV001134289 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212513 SCV001153832 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing

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