rs63750144
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.884G>A(p.Ser295Asn) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S295G) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense, splice_region
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
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. -
Lynch syndrome Pathogenic:1
Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 295 of the MLH1 protein (p.Ser295Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. 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 missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22949379, 26761715). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). ClinVar contains an entry for this variant (Variation ID: 90415). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 12200596). This variant is not present in population databases (gnomAD no frequency). -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.884G>A pathogenic mutation (also known as p.S295N), located in coding exon 10 of the MLH1 gene, results from a G to A substitution at nucleotide position 884. This alteration changes the serine at codon 295 to asparagine, an amino acid with highly similar properties. This mutation was identified in an Australian woman diagnosed with MSI-H colorectal cancer at age 35 and a separate colorectal primary tumor at age 41. Both tumors showed absent MLH1 staining on IHC (Ward R et al. J. Cancer Res. Clin. Oncol. 2002 Aug;128(8):403-11). This mutation alters the highly-conserved last base pair of coding exon 10, is predicted to significantly weaken the native splice donor site by multiple in silico splicing models, and has been shown to cause exon skipping in vitro (Thompson BA et al. Hum. Mutat. 2013 Jan;34(1):200-9). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at