ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.790+4A>C (rs267607786)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167140 SCV000217970 likely pathogenic Hereditary cancer-predisposing syndrome 2014-12-12 criteria provided, single submitter clinical testing The c.790+4A>C intronic variant results from an A to C substitution 4 nucleotides after coding exon 9 in the MLH1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.<span style="font-family:arial,sans-serif; font-size:9pt">To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 42000 alleles tested) in our clinical cohort.This alteration has been identified in an individual meeting diagnostic criteria for HNPCC/Lynch syndrome with a tumor demonstrating microsatellite instability (Ambry Internal Data).<span style="font-family:arial,sans-serif; font-size:9pt">In addition, two different alterations at the same location (c.790+4A>G and c.790+4A>T) have been identified in individuals meeting criteria for Lynch syndrome and have been shown to result in partial exon skipping of exons 9 and 10 (Bianchi F, Fam. Cancer 2011 Mar; 10(1):27-35;Wehner M, Hum. Mutat. 1997 ; 10(3):241-4;Pagenstecher C, Hum. Genet. 2006 Mar; 119(1-2):9-22.).This nucleotide position is highly conserved in through mammalian species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native donor splice site, but is predicted to weaken (but not abolish) the efficacy of the native donor splice site by BDGP; however, direct evidence is unavailable.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249935 SCV001423877 likely pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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