NM_000249.4:c.677+1G>C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.677+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000249.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.677+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 8 of the MLH1 gene. This alteration has been identified as somatic in conjunction with a somatic pathogenic MLH1 variant in a MSI-H colon tumor with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). Another alteration impacting the same donor site (c.677+1G>T) has been detected in a French family that met modified Amsterdam criteria (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13), and was also detected in several individuals whose tumors showed high microsatellite instability and negative BRAF V600E analyses (Domingo E et al. J Med Genet. 2004 Sep;41(9):664-8; Lagerstedt Robinson K et al. J Natl Cancer Inst. 2007 Feb 21;99(4):291-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
This variant causes a G to C nucleotide substitution at the +1 position of intron 8 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.