rs587779796
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000038.6(APC):c.5017G>A(p.Glu1673Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5017G>A | p.Glu1673Lys | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+11639G>A | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250204Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135246
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461780Hom.: 0 Cov.: 65 AF XY: 0.0000206 AC XY: 15AN XY: 727192
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2Benign:1
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
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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. -
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This missense variant replaces glutamic acid with lysine at codon 1673 of the APC 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 not been reported in individuals affected with APC-related disorders. This variant has been identified in 6/250204 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. -
not provided Uncertain:2
In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast and/or ovarian cancer (PMID: 28528518, 35534704); This variant is associated with the following publications: (PMID: 25257991, 25925381, 35534704, 28528518, 18199528) -
The APC c.5017G>A (p.Glu1673Lys) variant has been reported in the published literature in a patient with breast and/or ovarian cancer (PMID: 28528518 (2017)). The frequency of this variant in the general population, 0.000087 (3/34534 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. -
Carcinoma of colon Uncertain:1
The APC p.Glu1673Lys variant was identified in 2 of 226 proband chromosomes (frequency: 0.009) from individuals or families with breast cancer, ovarian cancer or T-cell lymphoma (Cock-Rada 2018, Schatz 2015). The variant was also identified in dbSNP (ID: rs587779796 as "With Pathogenic, Uncertain significance allele") and ClinVar (5x as uncertain significance by GeneDx, Ambry Genetics, Counsyl, Invitae, and Color Genomics). The variant was not identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, or Zhejiang University database. The variant was identified in control databases in 6 of 244982 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 3 of 33530 chromosomes (freq: 0.00009), European in 3 of 110694 chromosomes (freq: 0.00003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Glu1673 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Classic or attenuated familial adenomatous polyposis Uncertain:1
This missense variant replaces glutamic acid with lysine at codon 1673 of the APC 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/250204 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. -
APC-related disorder Uncertain:1
The APC c.5017G>A variant is predicted to result in the amino acid substitution p.Glu1673Lys. This variant has been reported as a germline alteration in a patient with hereditary breast and/or ovarian cancer (as a variant of uncertain significance), and has also been documented in a tumor sample from a patient with peripheral T-cell lymphoma (Cock-Rada et al. 2018. PubMed ID: 28528518; Schatz et al. 2014. PubMed ID: 25257991). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain, likely benign or benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127301/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at