chr5-112839514-T-A

Position:

• chr5-112839514-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000038.6(APC):​c.3920T>A​(p.Ile1307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,038 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association; risk factor criteria provided, conflicting classifications P:17 U:19 O:15
• Conservation: PhyloP100: 0.887

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007214457).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00124 (1809/1461874) while in subpopulation MID AF= 0.022 (127/5768). AF 95% confidence interval is 0.0189. There are 28 homozygotes in gnomad4_exome. There are 954 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 191 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.3920T>A	p.Ile1307Lys	missense_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3920T>A	p.Ile1307Lys	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00201 AC: 504 AN: 251040 Hom.: 7 AF XY: 0.00194 AC XY: 263 AN XY: 135676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000688

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00124 AC: 1809 AN: 1461874 Hom.: 28 Cov.: 33 AF XY: 0.00131 AC XY: 954 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000393

Gnomad4 OTH exome AF: 0.00334

GnomAD4 genome AF: 0.00126 AC: 191 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74402

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00314 Hom.: 8

Bravo AF: 0.00136

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00169 AC: 205

EpiCase AF: 0.00180

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity; association; risk factor

Submissions summary: Pathogenic:17 Uncertain:19 Other:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Uncertain:8 Other:2

risk factor, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 17, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 06, 2020	In the published literature, 6%-7% of Ashkenazi Jewish individuals are reported to carry this variant, with a much higher frequency found in cohorts of Ashkenazi Jewish individuals with a history of colorectal cancer and/or polyps (PMIDs: 11159880 (2001), 10938175 (2000), 9288102 (1997)). This variant is reported as a risk factor for colorectal neoplasia (PMIDs: 30152102 (2019), 29506128 (2018), 26421687 (2016), 26314409 (2016), 23896379 (2013)). The risk of colorectal cancer for Ashkenazi Jewish carriers of the p.Ile1307Lys APC variant is reported to be approximately twice that of the general population (PMID: 23576677 (2013)). While this variant has been associated with a moderately increased risk of colorectal cancer, it is important to note that the p.Ile1307Lys variant does not cause classic Familial Adenomatous Polyposis (FAP). The risk for cancers other than colorectal cancer, and the risk of colorectal cancer for groups other than the Ashkenazi Jewish population, have not been well established. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 27, 2017	- -
risk factor, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2015	This variant is denoted APC c.3920T>A at the DNA level and p.Ile1307Lys (I1307K) at the protein level, replacing an Isoleucine with a Lysine. APC Ile1307Lys is a common variant, observed at an allele frequency of 3.7% (371/10,138) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016) and in up to 11% of individuals in Ashkenazi Jewish cohorts in the literature (Liang 2013, Boursi 2013). A meta-analysis of epidemiologic studies of APC polymorphisms suggests that individuals of Ashkenazi Jewish ancestry who carry this variant have a 2-fold increased risk of colorectal cancer (Liang 2013). However, studies of this variant in other populations did not report an increased risk of colorectal cancer (Liang 2013); therefore, the clinical significance in individuals without Jewish ancestry is not clear at this time. In sum, we consider APC Ile1307Lys to be a risk allele. The National Comprehensive Cancer Network has management guidelines for individuals carrying the APC Ile1307Lys risk allele (NCCN). -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Established risk allele, criteria provided, single submitter	curation	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2023	The APC c.3920T>A; p.Ile1307Lys variant (rs1801155) has been reported extensively in the literature, and is listed in ClinVar (Variation ID: 822). One recent meta-analysis of 30 published population studies, all of which examined the association between p.Ile1307Lys and colorectal neoplasia, colorectal adenoma, and/or colorectal cancer, concluded that this variant confers a two-fold increased risk of developing a colorectal neoplasia to persons of Ashkenazi Jewish ancestry (Liang 2013 and references therein). However, the risk in other populations is unclear. Additionally, this variant is observed in the general population at an overall frequency of 0.19% (524/282418 alleles, including 7 homozygotes) in the Genome Aggregation Database. Due to the high frequency in the general population, this variant is considered likely benign for most populations, but confers an increased risk of cancer in individuals of Ashkenazi Jewish ancestry. References: Liang et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol. 2013 177(11):1169-1179. PMID: 23576677. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 09, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 28, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	APC: PS3, PM1, PS4:Moderate, BP1, BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial adenomatous polyposis 1 Pathogenic:6 Uncertain:4 Other:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 27, 2016	I1307K is associated with a 10-20% lifetime risk of developing colon cancer in individuals of Ashkenazi Jewish ancestry and is not known to cause classic or attenuated FAP. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 2021	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
association, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1307 of the APC protein (p.Ile1307Lys). This variant is present in population databases (rs1801155, gnomAD 4%), including at least one homozygous and/or hemizygous individual. This variant is found in ~10% of Ashkenazi Jewish individuals and ~3% of Sephardic Jewish individuals (PMID: 23896379). Other studies have reported a 6-7% frequency in Ashkenazi individuals (PMID: 9288102). This variant is found in ~28% of Ashkenazi Jewish individuals with familial colorectal cancer (PMID: 9288102). ClinVar contains an entry for this variant (Variation ID: 822). In a large meta-analysis involving ~10,000 cases and controls (PMID: 23576677), Ashkenazi Jewish individuals who carried the I1307K change had a significantly increased risk of colorectal cancer (OR=2.17, 95% CI=1.65-2.86). By contrast, the I1307K change did not appear to confer any additional risk of colorectal cancer in non-Ashkenazi Jewish individuals (OR=1.36, 95% CI=0.59-3.13). This DNA substitution converts an AAATAAAA sequence element into an extended tract of eight adenosine nucleotides (A8). The A8 mononucleotide tract created by this change has been shown to confer an increased propensity for somatic truncating mutations on this allele (PMID: 9751605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, this is a frequently observed variant that is associated with a 2-fold increased risk of colorectal cancer in the Ashkenazi Jewish population. An increased risk of colorectal cancer in individuals who are not of Ashkenazi Jewish ancestry has not been established. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC c.3920T>A (p.Ile1307Lys) variant was identified in 6 of 812 proband chromosomes (frequency: 0.007) from individuals or families with colorectal cancer and was present in 16 of 286 control chromosomes (frequency: 0.056) from healthy individuals (Fraying 1998, Nielsen 2005, Yantiss 2009). The p.Ile1307Lys variant was also identified in dbSNP (ID: rs1801155) as “With Pathogenic allele”; in NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 14 of 8600 European American alleles and was not found in 4404 African American alleles. In the Exome Aggregation Consortium database, the variant was identified 205 of 121054 chromosomes (frequency: 0.002), including 177 of 66620 alleles of European (Non-Finnish), 15 of 16502 of South Asian, 10 of 11546 of Latinos and 3 of 906 of Other alleles. The variant was not found in African, East Asian and Finnish populations. In the ClinVar database, the variant was identified by 8 submitters with conflicting classifications: classified as pathogenic by GeneReviews and by Ambry Genetics, (who used as assertion method the Ambry Genetics Dominant and X-linked criteria); GeneDx, Invitae, OMIM (2X) classified the variant as Risk Factor; Biesecker Laboratory ClinSeq Project-NHGRI classified the variant as Uncertain significance and ITMI did not provide a classification. The variant was identified in the UMD Colon cancer database and was classified as Neutral; in COSMIC it was identified in an adenocarcinoma tumour of the large intestine. In the InSIGHT database, the variant was identified 10X and classified as a low penetrance risk allele. The p.Ile1307 residue is not conserved in mammals and mouse has a valine at the 1307 position and fish and fruit fly carry the variant 1307Lys amino acid at this position, increasing the likelihood that this variant is benign. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant protein remains perfectly functional, yet the genetic alteration results in a small hypermutable region of DNA that may be prone to somatic mutations (Laken 1997). Several studies suggest that this variant increases risk of colon cancer. Woodage (1998) genotyped 5,081 Ashkenazi volunteers in a community survey, identifying 376 heterozygotes and 2 homozygotes (6.1%) and concluded that APC I1307K carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage also emphasized that the large majority of I1307K carriers would not develop cancer of the colon. In addition, Gryfe (1999) identified the APC I1307K allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC I1307K allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P = 0.01). Compared with non-carriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Fraying (1998), identified this variant in 3 individuals with multiple colonic adenomas, but also identified this variant in 8% of Ashkenazi controls from North London. In the most recent study (Boursi 2013), the variant was analyzed in 3305 Israelis undergoing colonoscopy; clinical data regarding potential risk factors were collected to determine if the p.Ile1307Lys variant was a risk factor in CRC in Ashkenazi Jews. This analysis included the prospective evaluation of 3305 consecutive Israeli subjects. Analysis consisted of high risk and average risk subjects. High risk (n=560) were diagnosed less than 60 years with family or personal history of CRC; Average risk (n=1779) were asymptomatic. It focused on a unique subpopulation of Ashkenazi Jews at average risk for CRC in order to assess the need to modify colonoscopy surveillanc -
not provided, no classification provided	literature only	GeneReviews	-	- -
Established risk allele, criteria provided, single submitter	clinical testing	New York Genome Center	May 26, 2023	The c.3920T>A p.(Ile1307Lys) variant identified in APC is a common variant with ~3.5% minor allele frequency in individuals of Ashkenazi Jewish ancestry (gnomAD v2.1 and v3.1.2). The variant affects a conserved residue located in beta-catening binding domain and changes the (A)3(T)(A)4 sequence element into an extended tract of adenosine nucleotides (A8) which might predispose to slippage of polymerase during DNA replication and confer increased propensity for somatic truncating mutations on the allele [PMID: 37076288]. It has been reported that individuals of Ashkenazi Jewish ancestry who carry the p.(Ile1307Lys) variant are 1.7-2.17 times more likely to develop colorectal neoplasia compared to non-carrier individuals [PMID: 23896379, 23576677, 12173321], hence this variant is classified as a risk allele for colorectal neoplasia in the Ashkenazi Jewish population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	This sequence change replaces Isoleucine with Lysine at codon 1307 of the APC protein. The isoleucine residue is mildly conserved among species and is located in a known functional domain of the protein. There is a big physiochemical difference between isoleucine and lysine (Grantham Score 102). This variant is listed in population databases (rs1801155, ExAC 0.3) and is a common finding in individuals of Ashkenazi (~6-10%) and Sephardic Jewish decent (~3%; PMID: 9288102, 23896379). APC c.3920T>A (p.Ile1307Lys, also known as I1307K) has been associated with colorectal cancer. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry and is present in ClinVar (ID: 822). Several large studies have showed increased risk for developing colorectal cancer in Ashkenazi Jewish population. However, the cancer risk remains unknown in individuals of non-Jewish descent. In summary, this variant is an established risk factor for colorectal cancer in Ashkenazi Jewish populations and variant of uncertain significance in other populations. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
risk factor, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 02, 2017	The c.3920T>A (p.Ile1307Lys) variant in the APC gene has been reported as a common risk allele associated with familial colorectal cancer in the Ashkenazi Jewish population [PMID 18770064, 24416237]. The c.3920T>A variant has been reported to result in an adenine replacing a thymine and creating an oligo-adenine (A8) tract that appears to be inherently prone to further somatic mis-pairing and slippage during DNA replication, thereby creating a frameshift change [PMID 9288102, 18770064 and 244162370]. However, this variant has also been reported at a high frequency, present in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of colorectal cancer [PMID: 9288102]. Isoleucine at amino acid position 1307 of the APC protein is weakly conserved during evolution. While not validated for clinical use, the SIFT and PolyPhen-2 algorithms predict this variant to be benign. Ashkenazi Jews who carry the p.Ile1307Lys variant are at increased risk for colorectal neoplasia: the risk for colorectal neoplasia in heterozygous Ashkenazi Jewish individuals was estimated to be between 1.7 to 2.17 compared to non carrier individuals [PMID 12173321, 23576677, 23896379]. This variant is classified as as a risk allele with an increased risk for colorectal neoplasia in the Ashkenazi Jewish population. However the risk in non Jewish populations has not been determined. -
Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:5 Uncertain:1 Other:2

Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 22, 2022	- -
Established risk allele, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2024	The p.I1307K alteration (also known as c.3920T>A) is located in coding exon 15 of the APC gene. This alteration is present in 6-10% of the Ashkenazi Jewish population and has been reported at even higher frequencies in Ashkenazi Jewish colorectal cancer (CRC) cohorts (Boursi B et al. Eur. J. Cancer. 2013 Nov;49:3680-5; Gryfe R et al. Am J. Hum. Genet. 1999 Feb;64:378-84; Syngal S et al. JAMA. 2000 Aug;284:857-60; Stern HS et al. Gasteroenterol. 2001 Feb;120:392-400). The magnitude of CRC risk associated with p.I1307K has been debated in the literature; however, a meta-analysis of data from numerous independent studies found that p.I1307K confers an increased lifetime risk for CRC in the Ashkenazi Jewish population (OR=2.17, 95% CI=1.64-2.86; Liang J et al. Am. J. Epidemiol. 2013 Jun;177:1169-79). Associations between p.I1307K and risk of CRC and other malignancies is not well defined risk in non-Ashkenazi Jewish populations (Liang J et al. Am. J. Epidemiol. 2013 Jun;177:1169-79; Leshno A et al. Int. J. Cancer. 2016 Mar;138:1361-7; Abdel-Malak C et al. Fam. Cancer. 2016 Jan;15:49-56). This alteration is considered a risk allele for colorectal cancer and is not known to be associated with polyposis. Although controversial, increased colonoscopic surveillance is an option for carriers of this mutation (Rennert G et al. Dis. Colon Rectum. 2005 Dec;48:2317-21). Clinical correlation is advised. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 05, 2019	- -
risk factor, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 10, 2017	- -
risk factor, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change replaces Isoleucine with Lysine at codon 1307 of the APC protein. The isoleucine residue is mildly conserved among species and is located in a known functional domain of the protein. There is a big physiochemical difference between isoleucine and lysine (Grantham Score 102). This variant is listed in population databases (rs1801155, ExAC 0.3) and is a common finding in individuals of Ashkenazi (~6-10%) and Sephardic Jewish decent (~3%; PMID: 9288102 ,23896379 ).Multiple studies have associated this variant with a moderate increase in the risk of colorectal cancer in individuals of Ashkenazi Jewish ancestry, in whom this variant is identified in 28% of cases with familial colorectal cancer (PMID: 9288102 ). In a recent meta-analysis the risk of colorectal cancer development was estimated to be increased 2-fold in Ashkenazi Jewish individuals carrying this variant, while this increase was not evident in other populations (PMID: 23576677). The mutation database ClinVar contains multiple entries for this variant (Variation ID:822). -
Established risk allele, no assertion criteria provided	clinical testing	Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	-	The c.3920T>A (p.Ile1307Lys) variant in the APC gene has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish population [PMID 18770064, 24416237]. This variant has also been reported at a high frequency, present in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of colorectal cancer [PMID: 9288102]. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. -
Established risk allele, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant replaces isoleucine with lysine at codon 1307 of the APC protein. This variant is common in the population and has been identified in 524/282418 chromosomes (0.19%) in the general population by the Genome Aggregation Database (gnomAD). In particular, this variant has been identified in 375/10358 Ashkenazi Jewish chromosomes (3.62%), including 7 homozygous individuals, by the Genome Aggregation Database (gnomAD). Several large case-control studies and meta-analyses have reported a slightly increased risk of colorectal cancer in Ashkenazi Jewish individuals who carried this p.Ile1307Lys variant: OR=1.51 [95% CI 1.16-1.98] (PMID: 23896379); OR=2.17 [95% CI 1.64-2.86] (PMID: 23576677); OR=2.53 [95% CI 2.11-3.04] (PMID: 26421687). However, the cancer risk remains unclear in individuals of non-Ashkenazi Jewish descent. One study has shown that this variant did not show significant association with colorectal cancer in non-Ashkenazi Jewish individuals (OR=1.36, 95% CI=0.59-3.13) (PMID: 23576677). -

Colorectal cancer Pathogenic:1 Uncertain:1 Other:1

risk factor, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2020	APC c.3920T>A (p.Ile1307Lys, also known as I1307K) has been associated with colorectal cancer. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (3.6% Genome Aggregation Database (gnomAD); rs1801155) and is present in ClinVar (ID: 822). Several large studies and meta-analyses have reported odds ratios 1.51-2.53 for developing colorectal cancer in Ashkenazi Jewish population (OR=1.51 [95% CI 1.16-1.98] Boursi 2013, OR=2.17 [95% CI 1.64-2.86] Liang 2013, OR=2.53 [95% CI 2.11-3.04] Leshno 2016). However, the cancer risk remains unknown in individuals of non-Jewish descent. This variant introduces a polyA(8) region that is subject to slippage during DNA replication, which increases the susceptibility for somatic changes (Laken 1997, Gryfe 1998). In summary, this variant is an established risk factor for colorectal cancer. -
Established risk allele, no assertion criteria provided	research	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC c.3920T>A (p.Ile1307Lys) variant was identified in 6 of 812 proband chromosomes (frequency: 0.007) from individuals or families with colorectal cancer and was present in 16 of 286 control chromosomes (frequency: 0.056) from healthy individuals (Fraying 1998, Nielsen 2005, Yantiss 2009). The p.Ile1307Lys variant was also identified in dbSNP (ID: rs1801155) as “With Pathogenic allele”; in NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 14 of 8600 European American alleles and was not found in 4404 African American alleles. In the Exome Aggregation Consortium database, the variant was identified 205 of 121054 chromosomes (frequency: 0.002), including 177 of 66620 alleles of European (Non-Finnish), 15 of 16502 of South Asian, 10 of 11546 of Latinos and 3 of 906 of Other alleles. The variant was not found in African, East Asian and Finnish populations. In the ClinVar database, the variant was identified by 8 submitters with conflicting classifications: classified as pathogenic by GeneReviews and by Ambry Genetics, (who used as assertion method the Ambry Genetics Dominant and X-linked criteria); GeneDx, Invitae, OMIM (2X) classified the variant as Risk Factor; Biesecker Laboratory ClinSeq Project-NHGRI classified the variant as Uncertain significance and ITMI did not provide a classification. The variant was identified in the UMD Colon cancer database and was classified as Neutral; in COSMIC it was identified in an adenocarcinoma tumour of the large intestine. In the InSIGHT database, the variant was identified 10X and classified as a low penetrance risk allele. The p.Ile1307 residue is not conserved in mammals and mouse has a valine at the 1307 position and fish and fruit fly carry the variant 1307Lys amino acid at this position, increasing the likelihood that this variant is benign. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant protein remains perfectly functional, yet the genetic alteration results in a small hypermutable region of DNA that may be prone to somatic mutations (Laken 1997). Several studies suggest that this variant increases risk of colon cancer. Woodage (1998) genotyped 5,081 Ashkenazi volunteers in a community survey, identifying 376 heterozygotes and 2 homozygotes (6.1%) and concluded that APC p.Ile1307Lys carriers have a modestly elevated risk of developing cancer (less than 2-fold). Woodage also emphasized that the large majority of p.Ile1307Lys carriers would not develop cancer of the colon. In addition, Gryfe (1999) identified the APC p.Ile1307Lys allele in 48 (10.1%) of 476 Ashkenazi Jewish subjects with adenomatous polyps and/or colorectal cancer. Compared with the frequency of 2 separate population control groups, the APC p.Ile1307Lys allele was associated with an estimated relative risk of 1.5 to 1.7 for colorectal neoplasia (P = 0.01). Compared with non-carriers, APC p.Ile1307Lys carriers had increased numbers of adenomas and colorectal cancers per patient, as well as a younger age at diagnosis. Fraying (1998), identified this variant in 3 individuals with multiple colonic adenomas, but also identified this variant in 8% of Ashkenazi controls from North London. In the most recent study (Boursi 2013), the variant was analyzed in 3305 Israelis undergoing colonoscopy; clinical data regarding potential risk factors were collected to determine if the p.Ile1307Lys variant was a risk factor in CRC in Ashkenazi Jews. This analysis included the prospective evaluation of 3305 consecutive Israeli subjects. Analysis consisted of high risk and average risk subjects. High risk (n=560) were diagnosed less than 60 years with family or personal history of CRC; Average risk (n=1779) were asymptomatic. It focused on a unique subpopulation of Ashkenazi Jews at average risk for CRC in order to assess the need to -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.3920T>A (p.Ile1307Lys) in APC gene has been reported previously in heterozygous state in multiple individuals affected with Colorectal cancer (Breen KE et al. 2022; Long JM et al. 2022). The p.Ile1307Lys variant has allele frequency 0.2% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Benign / Uncertain Significance / Risk factor / Established risk allele / Likely pathogenic / Pathogenic (multiple submiters). Multiple lines of computational evidence (Polyphen - Benign, SIFT -Tolerated and Mutation Taster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ile1307Lys in APC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 1307 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies related to this variant is unclear, the variant is enriched in patients with colorectal cancer in Ashkenazi Jewish population (Boursi B et al. 2013). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of colorectal cancer. -

not specified Uncertain:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2024	Variant summary: APC c.3920T>A (p.Ile1307Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 254250 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency within the Ashkenazi Jewish subpopulation is nearly 33-fold the estimated maximal expected allele frequency for a pathogenic variant in APC causing the Colorectal Cancer Risk phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi-Jewish origin. However, multiple case-control studies have reported this variant with increased risk for colorectal cancer within the Ashkenazi Jewish population (e.g. Laken_1997, Gryfe_1999, Drucker_2000, Shtoyerman-Chen_2001, Fidder_2005, Boursi_2013). c.3920T>A has also been reported in the literature in individuals affected with non-colorectal cancer phenotypes (e.g. Maxwell_2016, Feliubadalo_2017, Schubert_2019, Fanale_2020, Akcay_2020), however these reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer Risk. A large meta-analysis concluded that the variant increases the risk of colorectal cancer by approximately 2-fold in individuals of Ashkenazi Jewish ancestry (OR=2.17, 95% CI=1.65-2.86), however the variant was not associated with additional risk in Non-Ashkenazi Jewish individuals in this study (Liang_2013). Another large case-control study identified the variant as a risk factor for non-colorectal cancers in an Israeli population (Leshno_2016). Co-occurrences with other pathogenic variants have been reported [BRCA1 c.68_69del, p.E23VfsX17 (Yurgelun_2017); RAD51C c.630T>G, p.Tyr210X (internal sample); MSH6 c.3743_3744insT, p.Tyr1249LeufsTer26 (Zhang_2020)], providing some supporting evidence for a benign role, however most case-control studies in the Ashkenazi-Jewish population support classification of the variant as a risk-factor for colorectal cancer. While there is insufficient evidence to determine risk in individuals without Ashkenazi-Jewish heritage, in-vivo and in-vitro studies have indicated that this germline variant may result in a much more highly mutable allele by creating an (A)8 mononucloetide tract that has a higher propensity for somatic frameshift mutations (e.g. Laken_1997, Gryfe_1998). Current NCCN guidelines recommend colorectal cancer surveillance measures for carriers of this variant due to association with a higher colorectal cancer risk. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 30980208, 18343606, 23896379, 28749474, 11207040, 30152102, 10679643, 32854451, 28050010, 15929773, 9973276, 9751605, 26187149, 9288102, 26421687, 23576677, 27153395, 25604157, 27978560, 30814645, 30426508, 26394139, 26845104, 11551102, 26300997, 14633595, 29961768, 28135145, 24416237, 31444830). ClinVar contains an entry for this variant (Variation ID: 822). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Familial multiple polyposis syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 24, 2015	- -

Breast carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 09, 2021

Diagnosis: Breast Cancer Pathology: Invasive breast carcinoma(NST) IHC: ER:+ , PR:+ , HER2:+ , KI67:%20 -

APC-Associated Polyposis Disorders Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 11/13/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Familial colorectal cancer Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic "Moderate Risk Allele" and reported on 07-15-2020 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

FAMILIAL ADENOMATOUS POLYPOSIS 1, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2019

- -

Carcinoma of colon Other:1

risk factor, criteria provided, single submitter

research

Snyder Lab, Genetics Department, Stanford University

Jan 01, 2017

- -

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Colorectal cancer, susceptibility to Other:1

risk factor, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

Low penetrance mutation that is associated with a small increase in risk of colon cancer and with an increased risk of colon polyps (Boursi 2013) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.23
Sift	Benign	0.086	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.012	B;B
Vest4		0.21
MVP		0.88
ClinPred		0.0073	T
GERP RS		4.5
Varity_R		0.074
gMVP		0.64

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: rs1801155; hg19: chr5-112175211; COSMIC: COSV57326270; COSMIC: COSV57326270;