NM_000038.6:c.1958+3A>G

Variant names:

• chr5-112835168-A-G
• rs879254032
• NM_000038.6:c.1958+3A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000038.6(APC):​c.1958+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.50

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-112835168-A-G is Pathogenic according to our data. Variant chr5-112835168-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 245982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835168-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1958+3A>G		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1958+3A>G		splice_region_variant, intron_variant	Intron 15 of 15	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+6196A>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial multiple polyposis syndrome Pathogenic:2

Sep 23, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.1958+3A>G 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: Four predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping of legacy exon 14 (Aretz_2004). The variant was absent in 245248 control chromosomes. c.1958+3A>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Aretz_2004, Aceto_2005, Lagarde_2010, Rivera_2011). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Pathogenic:2

Jun 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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 alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 15459959, 24599579). ClinVar contains an entry for this variant (Variation ID: 245982). This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 14523376, 15459959, 20434453, 24599579). In at least one individual the variant was observed to be de novo. This sequence change falls in intron 15 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. -

May 03, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. -

not provided Pathogenic:2

Sep 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: exon skipping (Aretz et al., 2004b); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32635641, 20434453, 22736432, 20223039, 24599579, 14523376, 15459959, 16134147, 26446593, 20924072) -

Nov 21, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 28, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1958+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 14 in the APC gene. This alteration has been identified in numerous unrelated individuals with familial adenomatous polyposis (Ambry internal data; Lagarde A et al. J Med Genet, 2010 Oct;47:721-2; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114). It has been identified as a confirmed de novo alteration in one proband and in another it appeared in a non-familial FAP case suggesting de novo status (Aretz S et al. Eur J Hum Genet, 2004 Jan;12:52-8; Aretz S et al. Hum Mutat, 2004 Nov;24:370-80; Rivera B et al. Ann Oncol, 2011 Apr;22:903-909). This alteration has also been detected in familial FAP cases and segregates with disease (Aceto G et al. Hum Mutat, 2005 Oct;26:394; Aretz S et al. Eur J Hum Genet, 2004 Jan;12:52-8;). This alteration results in a transcript lacking exon 14 which leads to a frameshift (Aretz S et al. Hum Mutat, 2004 Nov;24:370-80; Grandval P et al. Hum. Mutat. 2014 May; 35(5):532-6; Castellsagué E et al. Gastroenterology, 2010 Aug;139:439-47, 447.e1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254032; hg19: chr5-112170865;