1-45331327-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001048174.2(MUTYH):āc.1247A>Gā(p.His416Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H416Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.1247A>G | p.His416Arg | missense_variant | 14/16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
ENSG00000288208 | ENST00000671898.1 | n.1835A>G | non_coding_transcript_exon_variant | 18/21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251492Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727248
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2023 | This missense variant replaces histidine with arginine at codon 444 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 MUTYH-related disorders in the literature. This variant has been identified in 2/251492 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 | Ambry Genetics | Aug 02, 2023 | The c.1331A>G (p.H444R) alteration is located in exon 14 (coding exon 14) of the MUTYH gene. This alteration results from a A to G substitution at nucleotide position 1331, causing the histidine (H) at amino acid position 444 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 30, 2024 | The MUTYH c.1331A>G (p.His444Arg) variant has been reported in the published literature in an individual with breast cancer as well as in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000008 (2/251492 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 05, 2023 | This variant is present in population databases (rs144309934, gnomAD 0.002%). 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: 142069). 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 sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 444 of the MUTYH protein (p.His444Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at