ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1626+3A>G

dbSNP: rs1060503372
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel RCV003148749 SCV003836586 likely pathogenic Familial adenomatous polyposis 1 2023-02-19 reviewed by expert panel curation The c.1626+3A>G variant in APC is an intronic variant which is located at the 3rd nucleotide in intron 13. This variant has been reported in 4 probands meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate, Ambry Genetics, GeneDX internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The results from more than or equal to 2 in silico splicing predictors indicate that this variant may affect splicing by disrupting the donor splice site of intron 13 of APC (PP3). This is confirmed by RT-PCR which demonstrate that the variant impacts splicing by leading to an in-frame exon skipping event in exon 13 r.1549_1626del78 (p.Ala517_Gln542del) (PS3_Moderate, Ambry internal data). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Invitae RCV003148749 SCV000552761 pathogenic Familial adenomatous polyposis 1 2023-02-06 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of familial adenomatous polyposis (Invitae). ClinVar contains an entry for this variant (Variation ID: 411555). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of skipping of exon 13, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491321 SCV000579879 pathogenic Hereditary cancer-predisposing syndrome 2021-10-01 criteria provided, single submitter clinical testing The c.1626+3A>G intronic pathogenic variant results from an A to G substitution 3 nucleotides after coding exon 12 in the APC gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001783 SCV001159427 uncertain significance not specified 2019-04-26 criteria provided, single submitter clinical testing The APC c.1626+3A>G variant (rs1060503372) has not been reported in the medical literature, but is listed as a variant of uncertain clinical significance in ClinVar (Variation ID: 411555). It is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. This variant is located at a highly conserved nucleotide adjacent to the splice consensus sequence, and computational algorithms (Alamut v.2.11) predict that it affects the nearby canonical splice donor. However, due to the limited information regarding this variant, its clinical significance cannot be determined with certainty.
Color Diagnostics, LLC DBA Color Health RCV000491321 SCV001356132 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-18 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the +3 position of intron 13 of the APC gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been observed in individuals showing features of familial adenomatous polyposis (communication with an external laboratory). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively due to the lack of understanding of the variant impact on RNA splicing. Therefore, this variant is classified as a Variant of Uncertain Significance.

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