chr1-45331847-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001048174.2(MUTYH):c.916C>G(p.Pro306Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,601,924 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. P306T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001048174.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1000C>G | p.Pro334Ala | missense_variant, splice_region_variant | 12/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.916C>G | p.Pro306Ala | missense_variant, splice_region_variant | 12/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1000C>G | p.Pro334Ala | missense_variant, splice_region_variant | 12/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.916C>G | p.Pro306Ala | missense_variant, splice_region_variant | 12/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000131 AC: 3AN: 228910Hom.: 0 AF XY: 0.0000161 AC XY: 2AN XY: 124154
GnomAD4 exome AF: 0.0000172 AC: 25AN: 1449684Hom.: 0 Cov.: 36 AF XY: 0.0000139 AC XY: 10AN XY: 719942
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
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 | Jan 11, 2024 | This missense variant replaces proline with alanine at codon 334 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 reported in an individual affected with multiple adenomatous and serrated polyps (PMID: 24470512). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 3/228910 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 | Invitae | Jan 26, 2024 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 334 of the MUTYH protein (p.Pro334Ala). This variant is present in population databases (rs587778537, gnomAD 0.006%). This missense change has been observed in individual(s) with multiple adenomatous and serrated polyps (PMID: 24470512). ClinVar contains an entry for this variant (Variation ID: 183823). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 20, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 20, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | This missense variant replaces proline with alanine at codon 334 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 reported in an individual affected with multiple adenomatous and serrated polyps (PMID: 24470512). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 3/228910 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 | May 24, 2024 | The p.P334A variant (also known as c.1000C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1000. The proline at codon 334 is replaced by alanine, an amino acid with highly similar properties. This alteration has previously been detected in an individual with greater than 10 colon polyps (Guarinos C, Clin. Cancer Res. 2014 Mar; 20(5):1158-68), and was also detected in 1/1231 colorectal cancer patients and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This alteration was identified in 2/1358 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). This variant was also reported in 5/60,466 breast cancer cases and in 5/53,461 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 30, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2018 | Variant summary: MUTYH c.1000C>G (p.Pro334Ala) results in a non-conservative amino acid change in the encoded protein sequence that lies 3 nucleotides away from an exon-intron junction. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 224868 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (1.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1000C>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis. However, these reports do not provide unequivocal conclusions about an association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Neoplasm of stomach;C0206711:Pilomatrixoma;C3272841:Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at