Submissions for variant NM_001127511.3(APC):c.-191T>C

dbSNP: rs879253783

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003743685	SCV000768181	pathogenic	Familial adenomatous polyposis 1	2024-01-19	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 27087319, 27343414). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-191T>C. ClinVar contains an entry for this variant (Variation ID: 243005). Studies have shown that this variant alters APC gene expression (PMID: 27087319). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001013699	SCV001174319	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	The c.-191T>C pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the APC gene. This pathogenic mutation results from a T to C substitution 191 bases upstream from the first translated codon. This alteration has been described in five families with clinically-confirmed gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). In all five of these families, the mutation was detected in the germline of all available affected individuals, and it was not detected in available unaffected individuals, showing strong segregation with disease (Repak R et al. Gastrointest. Endosc. 2016 Oct;84:718-25; Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). The alteration impacts a highly-conserved nucleotide within the YY1 binding motif of APC promoter 1B, and authors demonstrated disrupted protein binding associated with c.-191T>C. Furthermore, luciferase assay results showed significantly reduced promoter activity for this variant compared to wild type (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). This nucleotide position is highly conserved on limited sequence alignment. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001559545	SCV001781791	pathogenic	not provided	2021-02-05	criteria provided, single submitter	clinical testing	Describes a nucleotide substitution 191 base pairs upstream of the ATG translational start site of the APC promoter 1B region Published functional studies demonstrate a damaging effect: decreased YY1 binding and significantly reduced transcriptional activity compared to wild-type (Li 2016) Also defined as APC c.-30417T>C using an alternate reference sequence (NM_000038.5) This variant is associated with the following publications: (PMID: 32895333, 27087319, 27343414, 29968043)
CeGaT Center for Human Genetics Tuebingen	RCV001559545	SCV002821304	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	APC: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001559545	SCV004025013	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001013699	SCV004361310	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This variant is located in the 5' untranslated region of the APC gene. This variant is reported as c.-191T>C on an alternative transcript NM_001127511.3. A functional study has shown this variant results in significantly decreased transcriptional activity compared to wild type protein in colorectal cancer and gastric cancer cell lines (PMID: 27087319). This variant has been reported in individuals and families affected with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 2996804, 31409086). It has been shown that this variant segregates with GAPPS syndrome in numerous families (PMID: 2996804, 31409086). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV001290975	SCV000292336	pathogenic	Gastric adenocarcinoma and proximal polyposis of the stomach	2021-02-23	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000234996	SCV001423254	not provided	Familial adenomatous polyposis 1		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 02-21-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.