ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.187G>A (p.Asp63Asn) (rs63750850)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212515 SCV000211107 likely pathogenic not provided 2016-09-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.187G>A at the cDNA level, p.Asp63Asn (D63N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). MLH1 Asp63Asn was observed in a Hungarian family meeting Amsterdam I criteria and reported to co-segregate with disease in two family members with a history of early-onset colon cancer but was not present in seven unaffected family members (Papp 2007). Raschle et. al. (2002) showed that MLH1 Asp63Asn results in a dramatic reduction in MLH1 and PMS2 protein expression. In addition, another variant at the same residue, MLH1 Asp63Glu, is considered pathogenic by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT). MLH1 Asp63Glu has been reported to segregate with Lynch syndrome-related cancers in at least one family and has been shown to result in decreased MLH1 protein expression, deficient mismatch repair activity, and decreased nuclear localization of MLH1 and PMS2 (Raevaara 2005, Hardt 2011). MLH1 Asp63Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Asp63Asn occurs at a position that is conserved across species and is located in ATP-binding domain (Raevaara 2005). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we consider MLH1 Asp63Asn to be a likely pathogenic variant.
Ambry Genetics RCV000160535 SCV000215751 pathogenic Hereditary cancer-predisposing syndrome 2019-05-14 criteria provided, single submitter clinical testing The p.D63N pathogenic mutation (also known as c.187G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 187. The aspartic acid at codon 63 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported in a Hungarian family satisfying Amsterdam I criteria for HNPCC/Lynch syndrome (Papp J et al. World J. Gastroenterol. 2007 May; 13(19):2727-32). In this family, p.D63N segregated with disease, being detected in the affected proband (CRC at 25y) and his affected father (CRC at 40y) and was absent from 7 cancer-free relatives. This variant has also been identified in multiple individuals with tumors demonstrating loss of MLH1 and PMS2 by immunohistochemistry (Ambry internal data). An in vitro functional study reported that the p.D63N variant abolished ATP binding in the hMLH1 subunit, deleteriously affecting expression of the heterodimer (Räschle M et al. J. Biol. Chem. 2002 Jun;277:21810-20). This amino acid position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075399 SCV000696133 likely pathogenic Lynch syndrome 2019-02-26 criteria provided, single submitter clinical testing Variant summary: MLH1 c.187G>A (p.Asp63Asn) results in a conservative amino acid change located in the Histidine kinase/HSP90-like ATPase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246206 control chromosomes. c.187G>A has been reported in the literature in individuals affected with Lynch Syndrome (Papp_2007, Espenschied_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in dramatically reduced expression of both MLH1 and PMS2 proteins and reduced ATP'ase activity (Raschle_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000694220 SCV000822654 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-03-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 63 of the MLH1 protein (p.Asp63Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Lynch syndrome in a single family (PMID: 17569143). ClinVar contains an entry for this variant (Variation ID: 89920). Experimental studies have shown that this missense change results in reduced expression of the MLH1 and PMS2 proteins (PMID: 11948175). A different missense substitution at this codon (p.Asp63Glu) has been determined to be pathogenic (PMID: 16083711, 21120944, 17594722). This suggests that the aspartic acid residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000160535 SCV001340137 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing

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