Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_001048174.2(MUTYH):c.1333G>T(p.Ala445Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A445T) has been classified as Likely pathogenic.
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-45331241-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141614.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, Likely_pathogenic=2}.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.A473S variant (also known as c.1417G>T), located in coding exon 14 of the MUTYH gene, results from a G to T substitution at nucleotide position 1417. The alanine at codon 473 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -