5-112838399-C-G

Position:

• chr5-112838399-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.2805C>G​(p.Tyr935Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y935Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.44

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 235 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838399-C-G is Pathogenic according to our data. Variant chr5-112838399-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 186058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838399-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.2805C>G	p.Tyr935Ter	stop_gained	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.2805C>G	p.Tyr935Ter	stop_gained	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 05, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 186058). This premature translational stop signal has been observed in individuals with familial adenomatous polyposis (PMID: 1324223, 1944466, 8381579, 8990002, 10083733, 10094547, 10713886, 11748858, 11933206, 12007223, 12173026, 15024739, 15108288, 16088911, 16317745, 17411426, 20685668, 20924072, 26300997; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr935*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1909 amino acid(s) of the APC protein. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2019	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18554166, 16088911, 19822006, 17785554, 11933206, 16292097, 27978560, 16890597, 27705013, 8990002, 24233542, 24987355, 12007223, 28533537, 20223039, 26446593, 12173026, 16317745, 11748858, 15951963) -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Dec 17, 2015

- -

Gastric adenocarcinoma and proximal polyposis of the stomach Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 25, 2022

ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderated -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The p.Y935* pathogenic mutation (also known as c.2805C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 2805. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This mutation has been identified in numerous familial adenomatous polyposis (FAP) patients and families of various ethnicities to date (van der Luijt RB et al. Hum. Mutat. 1997;9:7-16; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Friedl W et al. Hered Cancer Clin Pract 2005 Sep;3:95-114; Kanter-Smoler G et al. BMC Med 2008 Apr;6:10; Mehenni H et al. Eur J Gastroenterol Hepatol, 2005 Dec;17:1407-12; Fodde R et al. Genomics, 1992 Aug;13:1162-8; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2; Wallis YL et al. J. Med. Genet., 1999 Jan;36:14-20; Papp J et al. Fam. Cancer, 2016 Jan;15:85-97). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.95, 0.94
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854575; hg19: chr5-112174096; COSMIC: COSV57324059; COSMIC: COSV57324059;