ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4399C>T (p.Pro1467Ser)

gnomAD frequency: 0.00002  dbSNP: rs749142480
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Total submissions: 9
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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 RCV000471930 SCV003836602 benign Familial adenomatous polyposis 1 2023-02-26 reviewed by expert panel curation The c.4399C>T variant in APC is a missense variant predicted to cause the substitution of Proline by Serine at amino acid position 1467 (p.Pro1467Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in a heterozygous state in 75 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data). In addition, it has also been observed in 1 patient with an alternate molecular basis for disease – a pathogenic MSH6 germline variant (BP5; Melbourne Internal data). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as the wild type (BS3_Supporting; PMID: 18199528). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnish) population, which is higher than the HCCP VCEP threshold (0.001%) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BS3_Supporting, BP1 and BP5 (VCEP Specification version 1, date of approval: 12/12/2022).
Invitae RCV003316572 SCV000552568 uncertain significance Familial adenomatous polyposis 1 2023-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1467 of the APC protein (p.Pro1467Ser). This variant is present in population databases (rs749142480, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18199528, 21859464). ClinVar contains an entry for this variant (Variation ID: 411419). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV000565410 SCV000667285 likely benign Hereditary cancer-predisposing syndrome 2022-05-25 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl RCV000471930 SCV000785085 uncertain significance Familial adenomatous polyposis 1 2017-04-10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000565410 SCV000903489 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-10 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 1467 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant retained >80% of wild-type activity via catenin-regulated transcription assay (PMID: 18199528). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 6/251166 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.
Sema4, Sema4 RCV000565410 SCV002532071 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-15 criteria provided, single submitter curation
GeneDx RCV002260641 SCV002540343 uncertain significance not provided 2022-06-20 criteria provided, single submitter clinical testing Observed in at least one individual with multiple colon polyps (Azzopardi 2008); Published functional study demonstrated p.P1467S suppresses beta-catenin-regulated transcription similar to wild-type (Azzopardi 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21859464, 18199528)
Fulgent Genetics, Fulgent Genetics RCV002481466 SCV002778077 uncertain significance Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach 2022-01-11 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003316572 SCV004020245 uncertain significance Familial adenomatous polyposis 1 2023-02-14 criteria provided, single submitter clinical testing 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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