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
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.
Ambry Genetics RCV000160534 SCV000212722 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing The p.V506A variant (also known as c.1517T>C), located in coding exon 13 of the MLH1 gene, results from a T to C substitution at nucleotide position 1517. The valine at codon 506 is replaced by alanine, an amino acid with similar properties. This alteration was identified in several individuals whose family history met Amsterdam I/II criteria for Lynch syndrome and/or tumors showed loss of MLH1 and/or PMS2 protein expression on immunohistochemistry (IHC) as well as high microsatellite instability (MSI-H) (Ambry internal data; Liu B et al. Nat. Med. 1996 Feb;2:169-74; ). This alteration has also been observed in an individual whose colorectal tumor demonstrated normal mismatch repair protein expression on IHC (Ambry internal data). Multiple yeast-based functional studies of this variant have demonstrated reduced binding of the V506A hMLH1 protein with hPMS2 when compared to wild-type hMLH1 (Guerrette S et al. J. Biol. Chem. 1999 Mar 5;274:6336-41; Kondo E et al. Cancer Res. 2003 Jun;63:3302-8; Shimodaira H et al. Nat. Genet. 1998 Aug;19:384-9). Further, multiple functional studies where cell lines were transfected with this alteration have been shown to exhibit reduced MLH1 expression; however, in vitro functional assays showed that mismatch repair activity was comparable to wild-type (Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41; Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174455 SCV000225761 uncertain significance not provided 2017-09-15 criteria provided, single submitter clinical testing
Invitae RCV000524242 SCV000543586 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-01 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). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000259153 SCV000601359 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000259153 SCV000885704 likely pathogenic not specified 2019-06-06 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, Liu 1996, Syngal 1999), and segregates with disease in several unrelated families (internal data, personal communication with GeneDx and Invitae). In vitro functional analyses demonstrate reduced protein expression, but close to wild-type mismatch repair activity (Hinrichsen 2013, Takahashi 2007). Additionally, yeast two hybrid assays have demonstrated reduced functional outputs (Kondo 2003, Shimodaira 1998). This variant is reported in ClinVar (Variation ID: 89757), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 506 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: 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. Hinrichsen I et al. Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. Clin Cancer Res. 2013 May 1;19(9):2432-41. 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. Liu B et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med. 1996 Feb;2(2):169-74. 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.
Color Health, Inc RCV000160534 SCV000911974 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-12 criteria provided, single submitter clinical testing This missense variant replaces valine with alanine at codon 506 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant reduced MLH1 protein expression (PMID: 9697702, 17510385, 23403630), disrupted PMS2 and EXO1 binding activity (PMID: 10037723, 12810663), and reduced dominant mutator effect (PMID: 9697702, 17510385). However, the impact of this variant on DNA mismatch repair activity remains unclear (PMID: 17510385, 23403630). This variant has been reported in individuals with Lynch Syndrome (PMID: 8574961, 18383312, 19250818, 22426235, 25980754). This variant has been identified in 1/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.

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