VCV000822187.9 - ClinVar

NM_000038.6(APC):c.1105TTG[1] (p.Leu370del)

Germline

Top reviewed classifications are shown here.

Submission summary:

3 submissions

3 submitters

2 conditions

Reviewed by expert panel

Uncertain significance

Feb 2023 by ClinGen InSiGH… FDA Recognized Database

for Familial adenomatous polyposis 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.1105TTG[1] (p.Leu370del)

Variation ID: 822187 Accession: VCV000822187.9

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 5q22.2 5: 112819137-112819139 (GRCh38) [ NCBI UCSC ] 5: 112154834-112154836 (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	Mar 16, 2020	May 1, 2024	Feb 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.1105TTG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Leu370del	inframe deletion
NM_000038.5:c.1108_1110del
NM_001127510.3:c.1105TTG[1]	NP_001120982.1:p.Leu370del	inframe deletion
NM_001127511.3:c.1051TTG[1]	NP_001120983.2:p.Leu352del	inframe deletion
NM_001354895.2:c.1105TTG[1]	NP_001341824.1:p.Leu370del	inframe deletion
NM_001354896.2:c.1105TTG[1]	NP_001341825.1:p.Leu370del	inframe deletion
NM_001354897.2:c.1135TTG[1]	NP_001341826.1:p.Leu380del	inframe deletion
NM_001354898.2:c.1030TTG[1]	NP_001341827.1:p.Leu345del	inframe deletion
NM_001354899.2:c.1021TTG[1]	NP_001341828.1:p.Leu342del	inframe deletion
NM_001354900.2:c.928TTG[1]	NP_001341829.1:p.Leu311del	inframe deletion
NM_001354901.2:c.928TTG[1]	NP_001341830.1:p.Leu311del	inframe deletion
NM_001354902.2:c.964-129_964-127del		intron variant
NM_001354903.2:c.934-129_934-127del		intron variant
NM_001354904.2:c.859-129_859-127del		intron variant
NM_001354905.2:c.757-129_757-127del		intron variant
NM_001354906.2:c.256TTG[1]	NP_001341835.1:p.Leu87del	inframe deletion
NC_000005.10:g.112819137TTG[1]
NC_000005.9:g.112154834TTG[1]
NG_008481.4:g.131617TTG[1]
LRG_130:g.131617TTG[1]

... more HGVS ... less HGVS

Protein change

L311del, L87del, L370del, L342del, L345del, L352del, L380del

Other names

NM_000038.6(APC):c.1105TTG[1]
p.Leu370del

Canonical SPDI

NC_000005.10:112819136:TTGTTG:TTG

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: rs1580529312 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	14981	15119

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 3, 2021	RCV001017338.7
Familial adenomatous polyposis 1	Uncertain significance (1)	reviewed by expert panel	Feb 18, 2023	RCV003148911.1

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.
Uncertain significance (Feb 18, 2023)	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1) Method: curation	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel FDA Recognized Database Accession: SCV003836576.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f51c0994-bf0d-42bc-b219-f1fe7018971c Comment: The c.1105TTG[1] or c.1108_1110del variant in APC is predicted to cause a change in the length of the protein due to an in-frame deletion of … (more) The c.1105TTG[1] or c.1108_1110del variant in APC is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Leu370del). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was not observed in internal data from Ambry Genetics, Invitae, Bonn or Melbourne. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PM2_Supporting (VCEP specifications version 1.0; date of approval: 12/12/2022). (less)
Uncertain significance (Jun 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001346380.3 First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022	Comment: This variant causes a deletion of 1 amino acid from the APC protein. To our knowledge, functional studies have not been reported for this variant. … (more) This variant causes a deletion of 1 amino acid from the APC protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 29, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001178410.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The c.1108_1110delTTG variant (also known as p.L370del) is located in coding exon 9 of the APC gene. This variant results from an in-frame TTG deletion … (more) The c.1108_1110delTTG variant (also known as p.L370del) is located in coding exon 9 of the APC gene. This variant results from an in-frame TTG deletion at nucleotide positions 1108 to 1110. This results in the in-frame deletion of a leucine at codon 370. This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The c.1105TTG[1] or c.1108_1110del variant in APC is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Leu370del). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was not observed in internal data from Ambry Genetics, Invitae, Bonn or Melbourne. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PM2_Supporting (VCEP specifications version 1.0; date of approval: 12/12/2022).

Comment:

This variant causes a deletion of 1 amino acid from the APC protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

The c.1108_1110delTTG variant (also known as p.L370del) is located in coding exon 9 of the APC gene. This variant results from an in-frame TTG deletion at nucleotide positions 1108 to 1110. This results in the in-frame deletion of a leucine at codon 370. This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f51c0994-bf0d-42bc-b219-f1fe7018971c	-	-	-	-

Text-mined citations for rs1580529312 ...

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 May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000038.6(APC):c.1105TTG[1] (p.Leu370del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1580529312 ...