ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.885-5G>T (rs267607802)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075917 SCV000106936 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Intronic substitution with no effect on splicing, tested with NMD inhibitor
GeneDx RCV000585990 SCV000211137 likely benign not provided 2021-02-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 12624141, 18561205, 22949379)
Ambry Genetics RCV000160558 SCV000216095 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intronic alteration with no splicing impact by rt-pcr analysis or other splicing assay;Other data supporting benign classification
Invitae RCV001080675 SCV000253145 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000417381 SCV000601414 likely benign not specified 2017-06-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160558 SCV000684879 benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585990 SCV000696187 likely benign not provided 2016-05-16 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.885-5G>T variant involves the alteration of a non-conserved intronic nucleotide. 3/5 splice prediction tools predict no significant impact on normal splicing. Functional analysis using the pCAS ex vivo splicing assay and RNA analysis demonstrated this variant had no effect (Tournier_2008), strongly supporting for benign outcome. This variant was found in 2/121336 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). However, the population data could still suggest it to be a rare polymorphism. It has been reported in one HNPCC family in literature without strong evidence for or against pathogenicity (Parc_2003). Multiple clinical labs as well as a reputable database has classified it as likely benign/neutral. Taken together, this variant has currently been classified as Likely Benign..
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585990 SCV000889408 likely benign not provided 2017-06-08 criteria provided, single submitter clinical testing
Mendelics RCV000987159 SCV001136390 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000585990 SCV001549002 likely benign not provided no assertion criteria provided clinical testing The MLH1 c.885-5G>T variant was identified in 1 of 872 proband chromosomes (frequency: 0.001) from French individuals or families with HNPCC (Parc 2003). The variant was also identified in dbSNP (ID: rs267607802) as “With other allele”, ClinVar (classified as likely benign by an InSiGHT expert panel (2013), GeneDx, Invitae, Ambry Genetics, and 3 other submitters; and as benign by Color), and UMD-LSDB (classified neutral). The variant was identified in control databases in 5 of 246182 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 1 of 33582 chromosomes (freq: 0.00003) and European Non-Finnish in 4 of 111640 chromosomes (freq: 0.00004), while it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The c.885-5G>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. However, one study using both a minigene assay and RT-PCR on patient RNA showed that this variant has no effect on splicing (Tournier 2008). 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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