NM_000249.4:c.588+5G>C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000249.4(MLH1):c.588+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1Uncertain:1
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This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205]. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 90286). 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). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
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. -
Lynch syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at