ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.977T>C (p.Val326Ala) (rs63751049)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000035356 SCV000604229 uncertain significance not specified 2016-12-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115490 SCV000187366 likely benign Hereditary cancer-predisposing syndrome 2017-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Does not segregate with disease in family study (genes with incomplete penetrance),No disease association in small case-control study
CSER_CC_NCGL; University of Washington Medical Center RCV000148617 SCV000190332 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Color RCV000115490 SCV000684887 likely benign Hereditary cancer-predisposing syndrome 2015-04-03 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000075951 SCV000296892 uncertain significance Lynch syndrome 2015-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000035356 SCV000149399 likely benign not specified 2018-02-23 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ITMI RCV000035356 SCV000085539 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000590380 SCV000696195 likely benign not provided 2016-10-14 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.977T>C (p.Val326Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 65/122538 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0033113 (3/906). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. This variant was found in affected family members from two HNPCC families, in two affected members from a family and in three affected members from another family (Spaepen 2006, Hardt 2011). Detailed genotypic and phenotypic information was not available to assert whether or not the variant cosegregated with disease. In contrast, in one family, this variant did not cosegregate with the disease: while one affected member was positive for the variant, other two affected members did not carry the variant (Pastrello 2011). In addition, tumor tissues from patients with this variant showed no loss of heterozygosity, or loss of expression of MLH1 or MSH2, or microsatellite instability (Dieumegard 2000, Spaepen 2006, Pastrello 2011, Hardt 2011). In vitro MMR and dominant mutator effect studies showed conflicting results (Shimodaira 1998, Trojan 2002, Takahashi 2007) and in vitro assay may not accurately represent biological function. However, the yeast two-hybrid assay showed hMLH1 V326A can interact with hPMS2 and hEXO1 (Kondo 2003) and the variant was shown to not affect normal splicing (Borras 2012). Furthermore, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as benign/likely benign. Taken together, this variant is classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075951 SCV000106969 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000524327 SCV000153900 benign Hereditary nonpolyposis colon cancer 2017-12-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035356 SCV000059004 likely benign not specified 2017-07-27 criteria provided, single submitter clinical testing MLH1 977T>C: Disclaimer: This variant has not undergone a full assessment. The following are preliminary notes: This variant was classified as VUS3 in 2011. It has a Max MAF in ExAC of 0.12% (20 alleles) and in gnomAD of 0.11% (34 alleles). Frequency too high for disease. It is classified in ClinVar as benign by InSiGHT and Invitae, Likely benign by Ambry and Pathway Genomics, and VUS by GeneDx, CHOP, CSER.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000035356 SCV000691852 uncertain significance not specified no assertion criteria provided clinical testing
Pathway Genomics RCV000144598 SCV000189925 likely benign Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
PreventionGenetics RCV000590380 SCV000805985 likely benign not provided 2017-02-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000035356 SCV000601421 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590380 SCV000888191 benign not provided 2017-04-20 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115490 SCV000886687 likely benign Hereditary cancer-predisposing syndrome 2018-09-27 no assertion criteria provided clinical testing

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