rs1060503318

Variant names:

• chr5-112835165-G-A
• rs1060503318
• NM_000038.6:c.1958G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112835165-G-A
• chr5-112835165-G-C
• chr5-112835165-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000038.6(APC):​c.1958G>A​(p.Arg653Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000579851: RNA studies have demonstrated that this alteration, as well as a close match alteration, c.1958G>T, results in abnormal splicing in the set of samples tested (Ambry internal data" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653G) has been classified as Pathogenic. The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.60
• Publications: 17 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000579851: RNA studies have demonstrated that this alteration, as well as a close match alteration, c.1958G>T, results in abnormal splicing in the set of samples tested (Ambry internal data; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2; Ambry internal data).; SCV001549475: In addition, in vitro analysis by RT-PCR and ex vivo analysis by Splicing reporter minigene pCAS, showed major loss of exon 14 during splicing (Grandval 2014).; SCV000768098: Studies have shown that this variant results in skipping of exon 15 (also known as exon 14) and introduces a new termination codon (PMID: 20685668, 24599579).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-112835164-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 428139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-112835165-G-A is Pathogenic according to our data. Variant chr5-112835165-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 428128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.1958G>A	p.Arg653Lys	missense splice_region	Exon 15 of 16	NP_000029.2
	APC	NM_001407446.1		c.2042G>A	p.Arg681Lys	missense splice_region	Exon 15 of 16	NP_001394375.1
	APC	NM_001354896.2		c.2012G>A	p.Arg671Lys	missense splice_region	Exon 16 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1958G>A	p.Arg653Lys	missense splice_region	Exon 15 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1958G>A	p.Arg653Lys	missense splice_region	Exon 16 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.*156G>A		splice_region non_coding_transcript_exon	Exon 11 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Carcinoma of colon (1)
1	-	-	Familial adenomatous polyposis 1 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.80		Gain of ubiquitination at R653 (P = 0.0198)
MVP		0.93
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.86
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 0

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

Other links and lift over

dbSNP: rs1060503318; hg19: chr5-112170862; COSMIC: COSV57333087;