Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_001128425.2(MUTYH):c.306C>T(p.Ser102Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
MUTYH Gene-Disease associations (from GenCC):
familial adenomatous polyposis 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
Our verdict: Benign. The variant received -11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 1-45333455-G-A is Benign according to our data. Variant chr1-45333455-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 492031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=2.39 with no splicing effect.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001128425.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
MUTYH
NM_001128425.2
MANE Plus Clinical
c.306C>T
p.Ser102Ser
synonymous
Exon 3 of 16
NP_001121897.1
MUTYH
NM_001048174.2
MANE Select
c.222C>T
p.Ser74Ser
synonymous
Exon 3 of 16
NP_001041639.1
MUTYH
NM_001293192.2
c.-55C>T
5_prime_UTR_premature_start_codon_gain
Exon 3 of 16
NP_001280121.1
Ensembl Transcripts
Selected
Gene
Transcript
Tags
HGVSc
HGVSp
Effect
Exon Rank
Protein
UniProt
MUTYH
ENST00000710952.2
MANE Plus Clinical
c.306C>T
p.Ser102Ser
synonymous
Exon 3 of 16
ENSP00000518552.2
MUTYH
ENST00000456914.7
TSL:1 MANE Select
c.222C>T
p.Ser74Ser
synonymous
Exon 3 of 16
ENSP00000407590.2
MUTYH
ENST00000372098.7
TSL:1
c.297C>T
p.Ser99Ser
synonymous
Exon 3 of 16
ENSP00000361170.3
Frequencies
GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
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.