Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001018388 | SCV001179620 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-25 | criteria provided, single submitter | clinical testing | The c.884+5T>C intronic variant results from a T to C substitution 5 nucleotides after coding exon 10 in the MLH1 gene. This variant was identified in an Argentinian family that either met Amsterdam II criteria, Bethesda guidelines, or had features suggestive of a dominant colorectal inheritance syndrome. (Rossi BM et al. BMC Cancer, 2017 Sep;17:623). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV002549476 | SCV003525051 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-08-16 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 822763). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28874130). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. |