5-112835109-T-G

Variant names:

• chr5-112835109-T-G
• rs876659460
• NM_000038.6:c.1902T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BP1

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.1902T>G (p.Ser634Arg) variant in APC is a missense variant predicted to cause substitution of Serine by Arginine at amino acid position 634 (p.Ser634Arg). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 0.5 (PS4 not met [Ambry]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID:27696107). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236788 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). RT-PCR of cDNA and mini-gene splicing assays demonstrated that the variant impacts splicing by skipping of exon 15 resulting in a premature stop codon (PMID:24599579). However, since alternative splicing/skipping of this exon is known and in PMID:24599579 no pronounced skipping compared to controls is described, PS3 is not applicable. Moreover, the results from ≥ 2 in silico splicing predictors (SpliceAI and MaxEntScan) support that this variant does not affect splicing. APC, in which the variant was identified, is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). Due to conflicting evidence, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PM2_Supporting, BP1 (VCEP specifications version v2.0.3; date of approval 7/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10578330/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 0.896
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP1: 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.1902T>G	p.Ser634Arg	missense	Exon 15 of 16	NP_000029.2
	APC	NM_001407446.1		c.1986T>G	p.Ser662Arg	missense	Exon 15 of 16	NP_001394375.1
	APC	NM_001354896.2		c.1956T>G	p.Ser652Arg	missense	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.1902T>G	p.Ser634Arg	missense	Exon 15 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1902T>G	p.Ser634Arg	missense	Exon 16 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.*100T>G		non_coding_transcript_exon	Exon 11 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251326 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	2	-	Familial adenomatous polyposis 1 (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.90
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.46		Loss of glycosylation at S634 (P = 0.0401)
MVP		0.92
ClinPred		0.98	D
GERP RS		1.8
Varity_R		0.96
gMVP		0.90
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs876659460; hg19: chr5-112170806;