ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1517T>C (p.Val506Ala) (rs63749909)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000174455 SCV000885704 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing The MLH1 c.1517T>C; p.Val506Ala variant has been described in individuals and families that met diagnostic criteria for Lynch syndrome (Chao 2008, Syngal 1999). Additionally, yeast two hybrid assays have demonstrated reduced functional outputs (Kondo 2003, Shimodaira 1998). However, the variant was shown to retain near wild-type mismatch repair activity (Takahashi 2007). This variant is reported in the ClinVar database (Variation ID: 89757), and is observed in the general population with a low overall allele frequency of 0.003% (1/30964 alleles) in the Genome Aggregation Database. The valine at codon 506 is well conserved across a variety of mammals, and computational programs (PolyPhen2, SIFT, MutationTaster) predict this variant to be deleterious. However, a panel of experts in the field, The International Society for Gastrointestinal Hereditary Tumors Incorporated (InSIGHT) have classified this variant as having uncertain significance due to insufficient evidence of pathogenicity (see link). Therefore, the clinical significance of this variant is uncertain at this time. REFERENCES Link to variant in InSIGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php?select_db=MLH1&action=search_all&search_Variant%2FDNA=c.1517T%3EC Chao EC et al. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat. 2008 Jun;29(6):852-60. Kondo E et al. A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 2003 Jun 15;63(12):3302-8. Shimodaira H et al. Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae. Nat Genet. 1998 Aug;19(4):384-9. Syngal S et al. Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA. 1999 Jul 21;282(3):247-53. Takahashi M et al. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007 May 15;67(10):4595-604.
Ambry Genetics RCV000160534 SCV000212722 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000160534 SCV000911974 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174455 SCV000225761 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing
GeneDx RCV000174455 SCV000211106 likely pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1517T>C at the cDNA level, p.Val506Ala (V506A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). MLH1 Val506Ala has been observed in multiple individuals with early onset colorectal cancer and in families meeting Amsterdam criteria (Liu 1996, Syngal 1999, Chao 2008). In addition, the variant has been observed at this laboratory to segregate with cancer in families whose histories are consistent with Lynch syndrome. Functional yeast-based assays of MLH1 Val506Ala demonstrated reduction in binding to PMS2 and EXO1 and a reduced dominant mutator effect in comparison to wild type (Shimodaira 1998, Guerrette 1999, Kondo 2003, Takahashi 2007). In vitro functional studies showed mismatch repair activity comparable to wild-type but reduced MLH1 expression (Takahashi 2007, Hinrichsen 2013). MLH1 Val506Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the domain of interaction with PMS2/MLH3/PMS1/EXO1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MLH1 Val506Ala to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000075231 SCV000919651 likely pathogenic Lynch syndrome 2017-12-21 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1517T>C (p.Va506Alal) involves the alteration of a mildly conserved nucleotide. 5/5 in silico tools predict deleterious outcome for this substitution and is located within C-terminal domain of DNA mismatch repair protein MLH1, which forms part of the endonuclease active site. The c.1517C>T is absent from the large control dataset of ExAC (~121410 chrs tested), but is present at a low frequency in gnomAD (0.00003230; 1/30964 chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007). The variant was detected in multiple CRC patients from families fulfilling the Amsterdam and the revised Bethesda criteria, however family members of these patients were not tested, therefore segregation of this variant with the disease is yet to be established. The variant displayed reduced MMR activity in multiple independent functional studies (Shimodaira_1999; Takahashi_2007; Hinrichsen_2013), altered binding to PMS2 (Guerette_1999) and reduced (20-50% of wt) expression of MLH1 (Shimodaira_1999; Hinrichsen_2013). Although compromised expression may subsequently result in reduced MMR activity, the possibility of destabilization effect of Val506Ala on the protein function cannot be completely ruled out (Hinrichsen_2013). Multiple clinical laboratories/diagnostic centers classify variant as VUS/Likely Pathogenic. Considering all, by applying ACMG rules (PS4, PM1, PM2, PP3) the variant is classified as Likely Pathogenic until more information becomes available.
Invitae RCV000524242 SCV000543586 likely pathogenic Hereditary nonpolyposis colon cancer 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 506 of the MLH1 protein (p.Val506Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families and individuals affected with Lynch syndrome (PMID: 8574961, 18383312, 10422993, Invitae). ClinVar contains an entry for this variant (Variation ID: 89757). Experimental studies have shown that this missense change reduces MLH1 expression and binding to PMS2 and EXO1, but does not affect MLH1 mismatch repair function (PMID: 9697702, 10037723, 12810663, 17510385, 23403630). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000259153 SCV000601359 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing

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