ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4813G>A (p.Val1605Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.4813G>A (p.Val1605Met)
Variation ID: 438880 Accession: VCV000438880.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112840407 (GRCh38) [ NCBI UCSC ] 5: 112176104 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 30, 2017 Jun 17, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.4813G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Val1605Met missense NM_001127510.3:c.4813G>A NP_001120982.1:p.Val1605Met missense NM_001127511.3:c.4759G>A NP_001120983.2:p.Val1587Met missense NM_001354895.2:c.4813G>A NP_001341824.1:p.Val1605Met missense NM_001354896.2:c.4867G>A NP_001341825.1:p.Val1623Met missense NM_001354897.2:c.4843G>A NP_001341826.1:p.Val1615Met missense NM_001354898.2:c.4738G>A NP_001341827.1:p.Val1580Met missense NM_001354899.2:c.4729G>A NP_001341828.1:p.Val1577Met missense NM_001354900.2:c.4690G>A NP_001341829.1:p.Val1564Met missense NM_001354901.2:c.4636G>A NP_001341830.1:p.Val1546Met missense NM_001354902.2:c.4540G>A NP_001341831.1:p.Val1514Met missense NM_001354903.2:c.4510G>A NP_001341832.1:p.Val1504Met missense NM_001354904.2:c.4435G>A NP_001341833.1:p.Val1479Met missense NM_001354905.2:c.4333G>A NP_001341834.1:p.Val1445Met missense NM_001354906.2:c.3964G>A NP_001341835.1:p.Val1322Met missense NC_000005.10:g.112840407G>A NC_000005.9:g.112176104G>A NG_008481.4:g.152887G>A LRG_130:g.152887G>A - Protein change
- V1587M, V1605M, V1445M, V1504M, V1546M, V1564M, V1322M, V1514M, V1580M, V1615M, V1479M, V1577M, V1623M
- Other names
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- Canonical SPDI
- NC_000005.10:112840406:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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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. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14931 | 15069 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2017 | RCV000506358.9 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000558695.17 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000580492.18 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 8, 2022 | RCV001591152.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 24, 2022 | RCV002289692.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 26, 2023 | RCV004003533.2 |
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. |
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000821816.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136918.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Mar 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600105.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
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Uncertain significance
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001824927.2
First in ClinVar: Sep 08, 2021 Last updated: Dec 24, 2022 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal or family history of breast and/or ovarian cancer (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 18199528, 31159747) (less)
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Uncertain significance
(Dec 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000681688.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with methionine at codon 1605 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with methionine at codon 1605 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders 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)
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Uncertain significance
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000647538.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1605 of the APC protein (p.Val1605Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1605 of the APC protein (p.Val1605Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 438880). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001184923.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.V1605M variant (also known as c.4813G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide … (more)
The p.V1605M variant (also known as c.4813G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 4813. The valine at codon 1605 is replaced by methionine, an amino acid with highly similar properties. This variant was reported as a variant of unknown significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gastric adenocarcinoma and proximal polyposis of the stomach
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580045.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM2_SUP, BP4
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Number of individuals with the variant: 1
Sex: female
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Uncertain Significance
(Jun 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004837971.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces valine with methionine at codon 1605 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 1605 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual with personal or family history of breast and/or ovarian cancer (PMID: 31159747). 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)
Number of individuals with the variant: 2
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Uncertain significance
(Jan 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005056294.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Text-mined citations for rs1554086219 ...
HelpRecord last updated Aug 18, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.