rs587778538
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001048174.2(MUTYH):c.953C>T(p.Ser318Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000348 in 1,609,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S318W) has been classified as Uncertain significance.
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.953C>T | p.Ser318Leu | missense_variant | Exon 12 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
ENSG00000288208 | ENST00000671898.1 | n.1541C>T | non_coding_transcript_exon_variant | Exon 16 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000538 AC: 13AN: 241834Hom.: 0 AF XY: 0.0000838 AC XY: 11AN XY: 131198
GnomAD4 exome AF: 0.0000364 AC: 53AN: 1457588Hom.: 0 Cov.: 33 AF XY: 0.0000524 AC XY: 38AN XY: 724770
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:4
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This missense variant replaces serine with leucine at codon 346 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 Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in two individual affected with breast and/or ovarian cancer (PMID: 25186627). This variant has been identified in 14/273222 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. -
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This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 346 of the MUTYH protein (p.Ser346Leu). This variant is present in population databases (rs587778538, gnomAD 0.04%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25186627, 25980754, 30982232). ClinVar contains an entry for this variant (Variation ID: 134862). 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:2Benign:1
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. -
This missense variant replaces serine with leucine at codon 346 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 Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in two individual affected with breast and/or ovarian cancer (PMID: 25186627). This variant has been identified in 14/273222 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. -
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not provided Uncertain:2
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Ser343Leu (c.1028C>T); This variant is associated with the following publications: (PMID: 24728327, 30982232, 36243179, 16879101, 20816984, 25980754, 25186627) -
The MUTYH c.1037C>T (p.Ser346Leu) variant has been reported in the published literature in individuals with breast cancer (PMID: 30982232 (2019), 25186627 (2015)) and a Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015)). This variant has also been identified in reportedly healthy individuals (PMID: 24728327 (2014), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). The frequency of this variant in the general population, 0.00037 (11/30074 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Uncertain:1Other:1
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Variant summary: MUTYH c.1037C>T (p.Ser346Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 241834 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (5.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.1037C>T has been reported in the literature in sequencing studies of individuals affected with and/or undergoing testing for breast cancer, colorectal cancer (example, Tung_2015, Yurgelun_2015, Wang_2019). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at