5-112819037-A-G
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
The NM_000038.6(APC):c.1005A>G(p.Leu335=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,098 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). Synonymous variant affecting the same amino acid position (i.e. L335L) has been classified as Likely benign.
Frequency
Consequence
NM_000038.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1005A>G | p.Leu335= | synonymous_variant | 10/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1005A>G | p.Leu335= | synonymous_variant | 10/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251080Hom.: 1 AF XY: 0.000162 AC XY: 22AN XY: 135690
GnomAD4 exome AF: 0.0000451 AC: 66AN: 1461830Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38AN XY: 727218
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74460
ClinVar
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2017 | Variant summary: The APC c.1005A>G (p.Leu335Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts the creation of SRp40 binding site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 41/276982 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001962 (37/18854). This frequency is about 27 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant was reported in one breast patient but also in controls (Chang_2016) and also as a somatic occurrence (Chang_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 27, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 10, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 17, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2015 | 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. - |
Familial adenomatous polyposis 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 29, 2024 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 19, 2013 | - - |
Carcinoma of colon Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC p.Leu335Leu variant was identified in 3 of 384 proband chromosomes (frequency: 0.0078125) from Taiwense individuals or families with CRC or breast cancer (Chang YC 2016, Chang YS 2016). There was found to be no observed association between breast cancer risk and the variant (Chang YS 2016). The variant was also identified in dbSNP (ID: rs3797704) “With Likely benign,other allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: benign by Invitae and GeneDx, likely benign by Ambry Genetics and Department of Pathology and Laboratory Medicine (Sinai Health System), and uncertain significance by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics)), Clinvitae (4x), Cosmic (2x in carcinomas of the large intestine), and Zhejiang Colon Cancer Database (1x), but was not identified in Genesight-COGR. The variant was identified in control databases in 40 of 276782 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: European Non-Finnish in 1 of 126350 chromosomes (frequency: 0.000008), East Asian in 37 of 1854 chromosomes (frequency: 0.002), and European Finnish in 2 of 25792 chromosomes (frequency: 0.00008). The p.Leu335= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Classic or attenuated familial adenomatous polyposis Benign:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at