VCV001070046.10 - ClinVar

NM_000038.6(APC):c.1958+2T>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.1958+2T>G

Variation ID: 1070046 Accession: VCV001070046.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112835167 (GRCh38) [ NCBI UCSC ] 5: 112170864 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 10, 2021	Feb 14, 2024	May 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.1958+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001127510.3:c.1958+2T>G		splice donor
NM_001127511.3:c.1904+2T>G		splice donor
NM_001354895.2:c.1958+2T>G		splice donor
NM_001354896.2:c.2012+2T>G		splice donor
NM_001354897.2:c.1988+2T>G		splice donor
NM_001354898.2:c.1883+2T>G		splice donor
NM_001354899.2:c.1874+2T>G		splice donor
NM_001354900.2:c.1835+2T>G		splice donor
NM_001354901.2:c.1781+2T>G		splice donor
NM_001354902.2:c.1685+2T>G		splice donor
NM_001354903.2:c.1655+2T>G		splice donor
NM_001354904.2:c.1580+2T>G		splice donor
NM_001354905.2:c.1478+2T>G		splice donor
NM_001354906.2:c.1109+2T>G		splice donor
NM_001407446.1:c.2042+2T>G		splice donor
NM_001407447.1:c.2012+2T>G		splice donor
NM_001407448.1:c.2012+2T>G		splice donor
NM_001407449.1:c.2012+2T>G		splice donor
NM_001407450.1:c.1958+2T>G		splice donor
NM_001407451.1:c.1937+2T>G		splice donor
NM_001407452.1:c.1928+2T>G		splice donor
NM_001407453.1:c.1781+2T>G		splice donor
NM_001407454.1:c.1709+2T>G		splice donor
NM_001407455.1:c.1709+2T>G		splice donor
NM_001407456.1:c.1709+2T>G		splice donor
NM_001407457.1:c.1709+2T>G		splice donor
NM_001407458.1:c.1655+2T>G		splice donor
NM_001407459.1:c.1655+2T>G		splice donor
NM_001407460.1:c.1655+2T>G		splice donor
NM_001407467.1:c.1571+2T>G		splice donor
NM_001407469.1:c.1571+2T>G		splice donor
NM_001407470.1:c.1109+2T>G		splice donor
NM_001407471.1:c.806+2T>G		splice donor
NM_001407472.1:c.806+2T>G		splice donor
NC_000005.10:g.112835167T>G
NC_000005.9:g.112170864T>G
NG_008481.4:g.147647T>G
LRG_130:g.147647T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000005.10:112835166:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2149844646 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APC		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	14965	15103

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial multiple polyposis syndrome	Likely pathogenic (1)	criteria provided, single submitter	Sep 1, 2022	RCV002298942.8
Familial adenomatous polyposis 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 3, 2023	RCV002550265.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Sep 01, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial multiple polyposis syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002599067.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Publications: PubMed (1) PubMed: 9950360 Comment: Variant summary: APC c.1958+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: APC c.1958+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247824 control chromosomes (gnomAD). c.1958+2T>G has been reported in the literature in at least one individual affected with Familial Adenomatous Polyposis (Wallis_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014 without providing evidence for independent evaluation: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (May 03, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004045663.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Publications: PubMed (1) PubMed: 15459959 Comment: This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an … (more) This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. (less)
Pathogenic (Mar 16, 2020)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001580676.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 9824584‚ 1316610‚ 27081525‚ 8381579‚ 22135120‚ 15311282‚ 17293347‚ 9950360‚ 20685668 Comment: For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs14) that lies downstream of this variant has been determined to be … (more) For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. Disruption of this splice site has been observed in individual(s) with familial adenomatous polyposis (PMID: 9950360, 20685668, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 15) of the APC gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. (less)

Comment:

Variant summary: APC c.1958+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247824 control chromosomes (gnomAD). c.1958+2T>G has been reported in the literature in at least one individual affected with Familial Adenomatous Polyposis (Wallis_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014 without providing evidence for independent evaluation: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959].

Comment:

For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. Disruption of this splice site has been observed in individual(s) with familial adenomatous polyposis (PMID: 9950360, 20685668, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 15) of the APC gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation.	Ikenoue T	Human genome variation	2015	PMID: 27081525
Prevalence of skin lesions in familial adenomatous polyposis: a marker for presymptomatic diagnosis?	Burger B	The oncologist	2011	PMID: 22135120
Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP.	Lagarde A	Journal of medical genetics	2010	PMID: 20685668
Regulated binding of adenomatous polyposis coli protein to actin.	Moseley JB	The Journal of biological chemistry	2007	PMID: 17293347
Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene.	Aretz S	Human mutation	2004	PMID: 15459959
EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration.	Wen Y	Nature cell biology	2004	PMID: 15311282
Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition.	Wallis YL	Journal of medical genetics	1999	PMID: 9950360
Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.	Brensinger JD	Gut	1998	PMID: 9824584
Mutational analysis of patients with adenomatous polyposis: identical inactivating mutations in unrelated individuals.	Groden J	American journal of human genetics	1993	PMID: 8381579
Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients.	Miyoshi Y	Proceedings of the National Academy of Sciences of the United States of America	1992	PMID: 1316610

Text-mined citations for rs2149844646 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000038.6(APC):c.1958+2T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2149844646 ...