chr1-45332182-C-T
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_001048174.2(MUTYH):c.833G>A(p.Cys278Tyr) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C278F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
Publications
- familial adenomatous polyposis 2Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
- colorectal cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- familial ovarian cancerInheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
- hereditary breast carcinomaInheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.833G>A | p.Cys278Tyr | missense_variant | Exon 10 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
ENSG00000288208 | ENST00000671898.1 | n.1421G>A | non_coding_transcript_exon_variant | Exon 14 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:4
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This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 306 of the MUTYH protein (p.Cys306Tyr). 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: 188158). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
This missense variant replaces cysteine with tyrosine at codon 306 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. 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). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
MUTYH-related disorder Uncertain:1
The MUTYH c.917G>A variant is predicted to result in the amino acid substitution p.Cys306Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org) and has been interpreted as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/188158/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.C306Y variant (also known as c.917G>A), located in coding exon 10 of the MUTYH gene, results from a G to A substitution at nucleotide position 917. The cysteine at codon 306 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at