Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2_SupportingPM5PP3_Moderate
The NM_001048174.2(MUTYH):c.1103G>T(p.Gly368Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G368D) has been classified as Likely pathogenic.
NM_001048174.2 missense, splice_region
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
GnomAD3 genomesCov.: 33 GnomAD4 exome AF: 6.84e-7AC: 1AN: 1461596Hom.: 0 AF XY: 0.00AC XY: 0AN XY: 727082
Submissions by phenotype
Familial adenomatous polyposis 2
|Uncertain significance, criteria provided, single submitter||clinical testing||Invitae||Feb 20, 2022||This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 396 of the MUTYH protein (p.Gly396Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 645786). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Gly396 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11818965, 16557584, 17489848, 19793053). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -|
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