ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.702G>A (p.Glu234=) (rs35908749)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030231 SCV000106840 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Synonymous substitution with no splicing aberration, treated with NMD inhibitor
GeneDx RCV000212521 SCV000170291 benign not specified 2014-01-23 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.
Ambry Genetics RCV000126773 SCV000212846 likely benign Hereditary cancer-predisposing syndrome 2014-08-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001082760 SCV000253142 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000126773 SCV000537423 likely benign Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588685 SCV000696177 likely benign not provided 2016-05-03 criteria provided, single submitter clinical testing Variant summary: This synonymous variant is located 25 nts downstream of intron-exon junction in coding region. 3/5 splice-site tools predict the variant not to have effect on splicing and two independent functional studies showed that this variant does not have effect on normal splicing (Borras et al 2012 and Thompson et al 2013). This variant has been reported in multiple HNPCC patients mostly of European origin, albeit some of them did not fulfilling Amsterdam criteria for HNPCC diagnosis. In one patient, another variant that could explain the phenotype was also detected. The variant was found at a frequency of 0.0392% in the general population (47/119650 chromosomes), clustered mainly in the population of European origin with no homozygous occurrence. This frequency in general population is lower than the maximal expected allele frequency (0.07%) for pathogenic MLH1 variant. Lastly, reputable databases and diagnostic centers classify the variant as likely benign/benign/neutral. Taken together, this variant has been classified as likely benign.
Mendelics RCV000987156 SCV001136383 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588685 SCV001153837 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987156 SCV001305704 uncertain significance Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000212521 SCV000691850 likely benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000126773 SCV000886686 likely benign Hereditary cancer-predisposing syndrome 2018-10-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356606 SCV001551822 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MLH1 p.Glu234Glu variant was identified in 5 of 1752 proband chromosomes (frequency: 0.003) from individuals or families with colon cancer or hereditary non-polyposis colorectal cancer and was not identified in 604 control chromosomes from healthy individuals (Borras 2012, Curia 1999, Grabowski 2004, Caldes 2002). The variant was also identified the following databases: dbSNP (ID: rs35908749) as “With Likely benign allele”, ClinVar (classified as benign 2x by GeneDx and Invitae; and classified as likely benign 4x by InSiGHT, Ambry Genetics, Color Genomics, Laboratory Corporation of America), Clinvitae (classified 2x as benign by GeneDx and Invitae; 4x as likely benign by Ambry Genetics, Color Genomics, InSiGHT, Laboratory Corporation of America), UMD-LSDB (observed 8x), Insight Colon Cancer Gene Variant Database (5x pathogenicity unknown, 1x probably no pathogenicity), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (6 references, all classified as “probably does not affect function”). The variant was not identified in COGR, COSMIC, MutDB, or the Zhejiang Colon Cancer Databases. The variant was identified in control databases in 110 of 276966 chromosomes at a frequency of 0.0004 in the following populations: Latino in 27 of 34398 chromosomes (freq. 0.0008); European non-Finnish in 67 of 126622 chromosomes (freq. 0.0005); South Asian in 10 of 30766 chromosomes (freq. 0.0003); population listed as Other in 2 of 6458 chromosomes (freq. 0.0003); and African in 3 of 23948 chromosomes (freq. 0.0001) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in a patient with endometrial cancer whose family meets Amsterdam criteria and was negative for MLH1 by IHC, however this variant did not affect mRNA processing or stability and the authors conclude that the variant is likely neutral (Borras 2012). Additionally, this patient was found to have two other MLH1 missense variants which resulted in exon 9 skipping and a truncated protein. This variant was also observed in a patient with colon cancer and resulted in a modest germline transcript unbalance in a primer extension assay (Curia 1999). The p.Glu234Glu variant is not expected to have clinical significance because it does not result in a change of amino acid. Three of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing however this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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