Submissions for variant NM_000249.4(MLH1):c.545+4_545+5del

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002651653	SCV003525324	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-06-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 26185136). ClinVar contains an entry for this variant (Variation ID: 2203328). 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 may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235775	SCV003934376	likely pathogenic	Hereditary nonpolyposis colon cancer	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.545+4_545+5delCA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant results in skipping of exon 6 (Yamaguchi_2015). The variant was absent in 251404 control chromosomes (gnomAD). c.545+4_545+5delCA has been reported in the literature in individuals affected with Lynch syndrome and colorectal cancer (example: Yamaguchi_2015 and Yamashita_2021). The following publications have been ascertained in the context of this evaluation (PMID: 26185136, 33746161). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.