ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.7036C>T (p.Pro2346Ser)
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.
Uncertain significance(5); Benign(4); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.7036C>T (p.Pro2346Ser)
Variation ID: 41512 Accession: VCV000041512.56
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112842630 (GRCh38) [ NCBI UCSC ] 5: 112178327 (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 Apr 12, 2013 Aug 4, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.7036C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Pro2346Ser missense NM_001127510.3:c.7036C>T NP_001120982.1:p.Pro2346Ser missense NM_001127511.3:c.6982C>T NP_001120983.2:p.Pro2328Ser missense NM_001354895.2:c.7036C>T NP_001341824.1:p.Pro2346Ser missense NM_001354896.2:c.7090C>T NP_001341825.1:p.Pro2364Ser missense NM_001354897.2:c.7066C>T NP_001341826.1:p.Pro2356Ser missense NM_001354898.2:c.6961C>T NP_001341827.1:p.Pro2321Ser missense NM_001354899.2:c.6952C>T NP_001341828.1:p.Pro2318Ser missense NM_001354900.2:c.6913C>T NP_001341829.1:p.Pro2305Ser missense NM_001354901.2:c.6859C>T NP_001341830.1:p.Pro2287Ser missense NM_001354902.2:c.6763C>T NP_001341831.1:p.Pro2255Ser missense NM_001354903.2:c.6733C>T NP_001341832.1:p.Pro2245Ser missense NM_001354904.2:c.6658C>T NP_001341833.1:p.Pro2220Ser missense NM_001354905.2:c.6556C>T NP_001341834.1:p.Pro2186Ser missense NM_001354906.2:c.6187C>T NP_001341835.1:p.Pro2063Ser missense NC_000005.10:g.112842630C>T NC_000005.9:g.112178327C>T NG_008481.4:g.155110C>T LRG_130:g.155110C>T LRG_130t1:c.7036C>T - Protein change
- P2346S, P2328S, P2063S, P2220S, P2287S, P2321S, P2255S, P2318S, P2364S, P2186S, P2245S, P2305S, P2356S
- Other names
- p.P2346S:CCA>TCA
- Canonical SPDI
- NC_000005.10:112842629:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00033
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD), exomes 0.00039
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00022
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 |
14938 | 15076 |
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 8, 2019 | RCV000120030.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2017 | RCV000515182.10 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 8, 2024 | RCV001083312.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 9, 2019 | RCV001153053.12 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jul 1, 2024 | RCV000034397.38 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Nov 15, 2022 | RCV000115118.23 |
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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Benign
(Feb 08, 2019)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363502.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: APC c.7036C>T (p.Pro2346Ser) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein … (more)
Variant summary: APC c.7036C>T (p.Pro2346Ser) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 275598 control chromosomes, predominantly at a frequency of 0.0074 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 104 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.7036C>T has been reported in the literature in individuals affected with different types of cancer, including pancreatic cancer and breast and/or ovarian cancer (Young_2018, Mandelker_2017, Yadav_2017, Maxwell_2016, Grant_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. A co-occurrence with another pathogenic variant has been reported in our internal database (APC c.1690C>T, p.Arg564*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (1x), likely benign (2x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Nov 11, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535180.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Sep 08, 2020)
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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: SCV000149027.15
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 24728327, 28873162, 22703879, 25203624, 27878467)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010860.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Benign
(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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219005.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
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Uncertain significance
(May 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Hepatocellular carcinoma Desmoid disease, hereditary Familial adenomatous polyposis 1 Familial adenomatous polyposis 1 Gastric cancer
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611341.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Likely benign
(Mar 28, 2018)
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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: SCV000681842.2
First in ClinVar: Feb 19, 2018 Last updated: May 19, 2019 |
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Uncertain significance
(Sep 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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APC-Associated Polyposis Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001314301.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Dec 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066576.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Nov 15, 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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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV002819218.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
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Benign
(Jan 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600143.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
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Likely benign
(May 02, 2019)
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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: SCV000172875.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Apr 08, 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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Myriad Genetics, Inc.
Accession: SCV005084460.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Likely benign
(Jul 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000609172.29
First in ClinVar: Oct 30, 2017 Last updated: Aug 04, 2024 |
Comment:
APC: BS1
Number of individuals with the variant: 14
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variant of unknown significance
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043137.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548588.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The APC p.Pro2346Ser variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0009) from individuals or families with atherosclerosis, unselected for personal or family … (more)
The APC p.Pro2346Ser variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0009) from individuals or families with atherosclerosis, unselected for personal or family histories of cancer (Johnston 2012). The variant was also identified in ClinVar (classified as uncertain significance by Quest Diagnostics, Fulgent Genetics and two other submitters; as likely benign by Ambry Genetics, GeneDx and Color; and as benign by Invitae) and LOVD 3.0 (1x as effect unknown/not classified). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 102 of 281270 chromosomes at a frequency of 0.0004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 80 of 10318 chromosomes (freq: 0.008), Other in 6 of 7184 chromosomes (freq: 0.0008), Latino in 4 of 35396 chromosomes (freq: 0.0001), and European (non-Finnish) in 12 of 127880 chromosomes (freq: 0.00009); it was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Pro2346 residue is conserved in mammals and 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 occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000084161.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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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Pancreatic cancer as a sentinel for hereditary cancer predisposition. | Young EL | BMC cancer | 2018 | PMID: 29945567 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Outcomes of retesting BRCA negative patients using multigene panels. | Yadav S | Familial cancer | 2017 | PMID: 27878467 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. | Grant RC | Gastroenterology | 2015 | PMID: 25479140 |
Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. | Carmi S | Nature communications | 2014 | PMID: 25203624 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Text-mined citations for rs200756935 ...
HelpRecord last updated Sep 29, 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.