rs748700385
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001048174.2(MUTYH):c.1193G>T(p.Arg398Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R398C) 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.1277G>T | p.Arg426Leu | missense_variant | 13/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1193G>T | p.Arg398Leu | missense_variant | 13/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1277G>T | p.Arg426Leu | missense_variant | 13/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1193G>T | p.Arg398Leu | missense_variant | 13/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251262Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135836
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 727234
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 426 of the MUTYH protein (p.Arg426Leu). This variant is present in population databases (rs748700385, gnomAD 0.003%). 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: 233962). 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 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 02, 2023 | This missense variant replaces arginine with leucine at codon 426 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 performed for this variant. In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/251262 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 | Dec 22, 2023 | The p.R426L variant (also known as c.1277G>T), located in coding exon 13 of the MUTYH gene, results from a G to T substitution at nucleotide position 1277. The arginine at codon 426 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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