ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.207+5G>C

dbSNP: rs587781518
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129504 SCV000184276 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-26 criteria provided, single submitter clinical testing The c.207+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 2 in the MLH1 gene. This alteration has been reported in an individual whose family history met Amsterdam criteria and who had an HNPCC-related tumor that was MLH1/PMS2-absent and microsatellite unstable (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471). Analysis of patient-derived RNA found that this alteration results in aberrant splicing leading to transcripts lacking coding exon 2 (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471). In addition, this alteration co-segregates with HNPCC-related tumors in multiple families (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000491027 SCV000579490 pathogenic Lynch syndrome 2016-03-25 criteria provided, single submitter clinical testing RNA evidence indicating exon 2 skipping and familial co-segregation analysis indicated evidence for cosegregation of this variant with colon cancers that have loss of MLH1 on IHC (likelihood ratio 25.28, LOD: 1.4). Taken together this is sufficient evidence for variant pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000129504 SCV001735150 likely pathogenic Hereditary cancer-predisposing syndrome 2020-12-01 criteria provided, single submitter clinical testing This variant causes a G to C nucleotide substitution at the +5 position of intron 2 of the MLH1 gene. A functional RNA study has shown that this variant causes out-of-frame skipping of exon 2, resulting in premature truncation (PMID: 27978560). This variant has been reported in two individuals affected with colorectal cancer that exhibited DNA mismatch repair deficient tumor pathology (PMID: 27978560, 32620519) and to cosegregate with disease in a family with multiple individuals affected with colorectal cancer (PMID: 27978560). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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