rs351771

Variant names:

• chr5-112828864-G-A
• rs351771
• NM_000038.6:c.1635G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112828864-G-A
• chr5-112828864-G-T
• chr5-112828864-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.1635G>A (p.Ala545=) variant is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.82 (15756 in 19198 alleles) in the East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.001) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP4, and BP7. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005411/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.60 (27988 hom., cov: 33)
  • Exomes 𝑓: 0.63 (289133 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign reviewed by expert panel B:20 O:1
• Conservation: PhyloP100: 1.61
• Publications: 73 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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1635G>A	p.Ala545Ala	synonymous	Exon 14 of 16	NP_000029.2
	APC	NM_001407446.1		c.1719G>A	p.Ala573Ala	synonymous	Exon 14 of 16	NP_001394375.1
	APC	NM_001354896.2		c.1689G>A	p.Ala563Ala	synonymous	Exon 15 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.1635G>A	p.Ala545Ala	synonymous	Exon 14 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1635G>A	p.Ala545Ala	synonymous	Exon 15 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000505084.2	TSL:1	n.1691G>A		non_coding_transcript_exon	Exon 14 of 14

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91390 AN: 151970 Hom.: 27971 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.613

GnomAD2 exomes AF: 0.649 AC: 162952 AN: 250988 AF XY: 0.649

Gnomad AFR exome AF: 0.532

Gnomad AMR exome AF: 0.733

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.628 AC: 911919 AN: 1453172 Hom.: 289133 Cov.: 31 AF XY: 0.630 AC XY: 455355 AN XY: 723316

African (AFR) AF: 0.518 AC: 17257 AN: 33304

American (AMR) AF: 0.726 AC: 32446 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 15137 AN: 26056

East Asian (EAS) AF: 0.840 AC: 33261 AN: 39600

South Asian (SAS) AF: 0.710 AC: 61080 AN: 86040

European-Finnish (FIN) AF: 0.572 AC: 30538 AN: 53342

Middle Eastern (MID) AF: 0.615 AC: 3525 AN: 5734

European-Non Finnish (NFE) AF: 0.616 AC: 680683 AN: 1104380

Other (OTH) AF: 0.633 AC: 37992 AN: 60038

GnomAD4 genome AF: 0.601 AC: 91459 AN: 152088 Hom.: 27988 Cov.: 33 AF XY: 0.603 AC XY: 44816 AN XY: 74320

African (AFR) AF: 0.534 AC: 22147 AN: 41462

American (AMR) AF: 0.669 AC: 10222 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1964 AN: 3470

East Asian (EAS) AF: 0.819 AC: 4247 AN: 5186

South Asian (SAS) AF: 0.732 AC: 3536 AN: 4830

European-Finnish (FIN) AF: 0.536 AC: 5660 AN: 10554

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41650 AN: 67984

Other (OTH) AF: 0.610 AC: 1287 AN: 2110

Alfa AF: 0.609 Hom.: 48720

Bravo AF: 0.610

Asia WGS AF: 0.754 AC: 2619 AN: 3476

EpiCase AF: 0.610

EpiControl AF: 0.612

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Familial adenomatous polyposis 1 (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	not provided (2)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		1.6
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs351771; hg19: chr5-112164561; COSMIC: COSV57321606;