rs587780083
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001048174.2(MUTYH):c.929_930delinsGC(p.Gln310Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q310H) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001048174.2 | c.929_930delinsGC | p.Gln310Arg | missense_variant | 12/16 | ENST00000456914.7 | |
MUTYH | NM_001128425.2 | c.1013_1014delinsGC | p.Gln338Arg | missense_variant | 12/16 | ENST00000710952.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.929_930delinsGC | p.Gln310Arg | missense_variant | 12/16 | 1 | NM_001048174.2 | A1 | |
MUTYH | ENST00000710952.2 | c.1013_1014delinsGC | p.Gln338Arg | missense_variant | 12/16 | NM_001128425.2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2023 | Variant summary: MUTYH c.1013_1014delinsGC (p.Gln338Arg) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 263932 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00013 vs 0.0046), allowing no conclusion about variant significance. c.1013_1014delinsGC has been reported in the literature in individuals affected with breast and colon cancer (example: Tung_2016, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. Functional evaluation of Gln338Arg (based on a different nucleotide change in at least one study) showed the variant, despite a reduced glycosylase activity, was able to complement for E. coli MutY in the rifampicin assay suggesting the enzyme to be functionally able to reduce mutations (example: Kundu_2009, Komine_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 15, 2017 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 30, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2020 | This variant is associated with the following publications: (PMID: 26976419, 27153395, 25820570, 19836313) - |
Familial adenomatous polyposis 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at