Total submissions: 3
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, |
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, |
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. |