chr1-45331223-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001048174.2(MUTYH):c.1351G>A(p.Glu451Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E451E) has been classified as Likely benign.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1435G>A | p.Glu479Lys | missense_variant | 14/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1351G>A | p.Glu451Lys | missense_variant | 14/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1435G>A | p.Glu479Lys | missense_variant | 14/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1351G>A | p.Glu451Lys | missense_variant | 14/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251492Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135920
GnomAD4 exome AF: 0.0000930 AC: 136AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This missense variant replaces glutamic acid with lysine at codon 479 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified as a heterozygous variant in two related individuals affected with polyposis (PMID: 20618354) and an individual affected with colorectal cancer (PMID: 21901162). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 11/282904 chromosomes 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Mar 25, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 479 of the MUTYH protein (p.Glu479Lys). This variant is present in population databases (rs376790729, gnomAD 0.008%). This missense change has been observed in individual(s) with multiple colon adenomas (PMID: 20618354). ClinVar contains an entry for this variant (Variation ID: 186129). 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 tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 29, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2023 | The p.E479K variant (also known as c.1435G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1435. The glutamic acid at codon 479 is replaced by lysine, an amino acid with similar properties. This alteration was found in an individual with 10 to 100 adenomas at age 41 and also in her daughter, who was affected with 20 to 30 adenomas first diagnosed in her teens. A second MUTYH alteration was not identified in this patient (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). Of note, this alteration is also known as c.1393G>A (p.Glu465Lys) in published literature. This amino acid position is not well conserved in available vertebrate species. 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 30, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 08, 2023 | This missense variant replaces glutamic acid with lysine at codon 479 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified as a heterozygous variant in two related individuals affected with polyposis (PMID: 20618354) and an individual affected with colorectal cancer (PMID: 21901162). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 11/282904 chromosomes 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2022 | Observed without a second MUTYH variant two related individuals with multiple adenomas and in an individual with soft tissue sarcoma (Morak et al., 2010; Ballinger et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as Glu476Lys; This variant is associated with the following publications: (PMID: 27498913, 20618354, 23108399) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at