Submissions for variant NM_000038.6(APC):c.1312+5G>A

dbSNP: rs886039507

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003476101	SCV000552563	pathogenic	Familial adenomatous polyposis 1	2021-11-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 exon 10 (also referred to as exon 9) and introduces a premature termination codon (PMID: 15459959, 22987206). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 411416). This variant has been observed in individuals with familial adenomatous polyposis (PMID: 15459959, 20223039, 22987206). 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 falls in intron 10 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 may result in an absent or disrupted protein product.
Ambry Genetics	RCV000490993	SCV000579784	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-29	criteria provided, single submitter	clinical testing	The c.1312+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 9 in the APC gene. This mutation has been detected in individuals with clinical diagnoses of familial adenomatous polyposis (FAP) and attenuated FAP (Ambry internal data; Aretz et al. Hum Mutat. 2004 Nov;24(5):370-80; Mihalatos M et al. BMC Cancer 2005 Apr;5:40; Schwarzova et al. Fam Cancer. 2013 Mar;12(1):35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). RNA analysis reveals that this mutation leads to substantially increased exon 9 skipping relative to control RNA samples (Ambry internal data; Aretz et al. Hum Mutat. 2004 Nov;24(5):370-80; Mihalatos M et al. BMC Cancer 2005 Apr;5:40; Schwarzova et al. Fam Cancer. 2013 Mar;12(1):35-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985284	SCV001133298	pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing	A splicing study showed that this variant produced a shift of frame, and is therefore predicted to result in the loss of a functional protein. Not found in the gnomAD dataset, and the data is high quality (0/34534 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192946	SCV001361420	pathogenic	Familial multiple polyposis syndrome	2019-07-10	criteria provided, single submitter	clinical testing	Variant summary: APC c.1312+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. Several publications report experimental evidence that this variant affects mRNA splicing, resulting in skipping of exon 9 and truncation of the protein (Aretz_2004, Mihalatos_2005, Schwarzova_2013). The variant was absent in 250464 control chromosomes. c.1312+5G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis(FAP) or Attenuated Familial Adenomatous Polyposis(AFAP) (Aretz_2004, Mihalatos_2005, Schwarzova_2013, Yanus_2018). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments of pathogenic for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000490993	SCV002053495	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the APC gene. RNA studies show that this variants resulted in exon 10 skipping (PMID: 8125478, 15459959, 15833136, 19196998, 22987206). This variant has been reported in individuals affected with familial adenomatous polyposis or colonic polyposis (PMID: 8125478, 15459959, 15833136, 22987206, 29029407, 29406563). It has been shown that this variant segregates with disease (PMID: 8125478). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics	RCV003476101	SCV004200385	pathogenic	Familial adenomatous polyposis 1	2021-09-16	criteria provided, single submitter	clinical testing