Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
A. |
RCV000075775 | SCV000914316 | uncertain significance | Lynch syndrome | 2019-01-30 | criteria provided, single submitter | research | |
Mendelics | RCV000987153 | SCV001136379 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001045347 | SCV001209189 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-08-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 32363481). ClinVar contains an entry for this variant (Variation ID: 90286). This variant has been observed in individuals with Lynch syndrome (PMID: 18389388, 26437257, 32363481). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |
Ambry Genetics | RCV002354265 | SCV002652822 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-05 | criteria provided, single submitter | clinical testing | The c.588+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 7 in the MLH1 gene. This variant has been detected in two affected individuals from a family meeting Amsterdam criteria for Lynch syndrome with tumor analysis revealing absence of MLH1 protein expression on immunohistochemistry and high microsatellite instability (MSI-H) (Goldberg Y et al. Fam. Cancer, 2008 Apr;7:309-17). A similar alteration at this position, c.588+5G>A, has also been shown to lead to the skipping of coding exon 7 and a truncated protein product (Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22; Tournier et al. Human Mutation. 2008. 29(12),1412-1424; Petersen SM et al. BMC Medical Genetics 2013,14:103). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Myriad Genetics, |
RCV000987153 | SCV004186527 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-17 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205]. |