ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2309C>G (p.Ser770Ter)

dbSNP: rs1060503310
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003766577 SCV000552607 pathogenic Familial adenomatous polyposis 1 2023-05-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. ClinVar contains an entry for this variant (Variation ID: 411447). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 7746201, 14522379, 20685668). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser770*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2074 amino acid(s) of the APC protein.
Counsyl RCV000461862 SCV000677765 pathogenic Familial adenomatous polyposis 1 2017-03-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002446835 SCV002735575 pathogenic Hereditary cancer-predisposing syndrome 2021-08-12 criteria provided, single submitter clinical testing The p.S770* pathogenic mutation (also known as c.2309C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 2309. This changes the amino acid from a serine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 2074 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Additionally, this mutation has been reported in multiple unrelated FAP families (Walpole IR et al. Med J Aust, 1995 May;162:464-7; Thomas D et al. Eur J Cancer, 2003 Oct;39:2200-4; Lagarde A et al. J Med Genet, 2010 Oct;47:721-2). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV000461862 SCV004020256 pathogenic Familial adenomatous polyposis 1 2023-02-14 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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