ClinVar Genomic variation as it relates to human health
NM_006296.7(VRK2):c.*102_*105dup
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(9); Benign(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006296.7(VRK2):c.*102_*105dup
Variation ID: 210988 Accession: VCV000210988.64
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 2p16.1 2: 58159793-58159794 (GRCh38) [ NCBI UCSC ] 2: 58386928-58386929 (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 29, 2015 Aug 4, 2024 Feb 1, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- T372fs, T367fs, T382fs, T387fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:58159793:TAATT:TAATTAATT
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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
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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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FANCL | - | - |
GRCh38 GRCh37 |
688 | 761 | |
VRK2 | - | - |
GRCh38 GRCh37 |
28 | 100 |
Conditions - Germline
Condition
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 22, 2022 | RCV000192919.13 | |
Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000513086.39 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000986760.3 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2022 | RCV001195069.11 | |
FANCL-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV003401051.5 |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 31, 2024 | RCV000226300.21 |
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
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135876.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Aug 02, 2019)
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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: SCV000247355.2
First in ClinVar: Oct 05, 2015 Last updated: Jun 12, 2020 |
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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: SCV002011559.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Benign
(Feb 22, 2022)
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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: SCV002103929.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: FANCL c.1096_1099dupATTA (p.Thr367AsnfsX13) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of … (more)
Variant summary: FANCL c.1096_1099dupATTA (p.Thr367AsnfsX13) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.003 in 249062 control chromosomes in the gnomAD database, including 4 homozygotes. Truncations downstream of this variant have not been observed at our laboratory and not reported in association with Fanconi Anemia in the HGMD/LOVD database. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCL causing Fanconi Anemia phenotype (0.00028), strongly suggesting that the variant is benign. Although widely reported in the literature, to our knowledge, no penetrant association of c.1096_1099dupATTA in individuals affected with Fanconi Anemia and no supporting experimental evidence demonstrating its impact on protein function have been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and one submitter reporting a pathogenic classification has since re-classified it internally as Benign (Benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as benign. (less)
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Uncertain significance
(Apr 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group L
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002320677.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
FANCL NM_018062.3 exon 14 p.Thr367Asnfs*13 (c.1096_1099dup): This variant has been reported in the literature in the compound heterozygous state in one individual with mild features … (more)
FANCL NM_018062.3 exon 14 p.Thr367Asnfs*13 (c.1096_1099dup): This variant has been reported in the literature in the compound heterozygous state in one individual with mild features of fanconi anemia (Ali 2009 PMID:19405097). It has also been reported in the heterozygous state in association with multiple different types of cancers (breast, lung adendocarcinoma, pediatric solid tumors, esophageal, head and neck squamous cell carcinoma) (Akbari 2011 PMID:21279724, Lhota 2016 PMID:26822949, Parsons 2016 PMID:26822237, Chandrasekharappa 2017 PMID:28678401, Ghazani 2017 PMID:28125075, del Valle 2020 PMID:32235514). However, this variant is also present in 0.4% (287/67948) of European alleles in the Genome Aggregation Database, including 3 homozygotes (https://gnomad.broadinstitute.org/variant/2-58159793-G-GTAAT?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:210989). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a frameshift variants that removes the final termination codon and extends out the protein. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Likely benign
(Jun 04, 2021)
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criteria provided, single submitter
Method: curation
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527272.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group L
Affected status: unknown
Allele origin:
maternal
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Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002567936.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Number of individuals with the variant: 1
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Uncertain significance
(Jun 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group L
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003833934.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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FANCL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004110518.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The FANCL c.1111_1114dupATTA variant is predicted to result in a frameshift and premature protein termination (p.Thr372Asnfs*13). In the literature, this variant is also referred to … (more)
The FANCL c.1111_1114dupATTA variant is predicted to result in a frameshift and premature protein termination (p.Thr372Asnfs*13). In the literature, this variant is also referred to as c.1095_1908dupAATT (p.Thr367Asnfs*13) and c.1111_1114dup p.(Thr372Asnfs*13).This variant has been reported in the heterozygous state in an individual with esophageal squamous cell carcinoma (ESCC) and a family history of ESCC (Patient P28266, Akbari et al. 2011. PubMed ID: 21279724) and in an individual with ovarian cancer (Patient ID 13-285, Bonache et al. 2018. PubMed ID: 30306255). This variant was also identified in several individuals in a study of variants in Fanconi anemia genes in hereditary cancer patients, however this study considered the cancer risk cancer for monoallelic carriers of this variant to be limited (Supplementary Tables, Del Valle et al. 2020. PubMed ID: 32235514). In a study of individuals with primary ovarian insufficiency, this variant was found in the homozygous and heterozygous states in individuals with no clinical features of Fanconi anemia and this variant was thought to be unlikely causative of the ovarian phenotype in these individuals (Table 3, POI-24 and POI-44, Franca et al. 2020 PubMedID: 33095795). This variant was also reported in a cohort of Fanconi anemia patients and another cohort of hereditary breast and ovarian cancer patients, however this variant was reported to be co-inherited with variants in other genes (Supplementary Tables 3 and 4, Chandrasekharappa et al. 2017. PubMed ID: 28678401; Supplementary Table 3, Tedaldi et al. 2017. PubMed ID: 28423363). This variant is reported in 0.68% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/210988/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000290416.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Fanconi Anemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000431329.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.1111_1114dupATTA (p.Thr372AsnfsTer13) variant, which results in a frameshift near the C-terminus of the protein and extends the full-length protein by ten amino acids, was … (more)
The c.1111_1114dupATTA (p.Thr372AsnfsTer13) variant, which results in a frameshift near the C-terminus of the protein and extends the full-length protein by ten amino acids, was observed in a patient with clinical features suggestive of Fanconi anemia (Ali et al. 2009). This patient was compound heterozygous for the p.Thr372AsnfsTer13 variant, which was inherited from the patient's father, and a second inframe deletion variant that was inherited from the patient's mother. Functional testing of this variant, when ectopically expressed in FA-L patient cell line, resulted in a phenotype intermediate of EUFA868 cells expressing vector alone and EUFA868 cells expressing wild-type FANCL. The p.Thr372AsnfsTer13 variant has been reported at a frequency of 0.00783 in the population described as 'Other' in the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Thr372AsnfsTer13 variant is classified as a variant of uncertain significance but suspicious for pathogenicity for Fanconi anemia. (less)
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Uncertain significance
(Aug 01, 2023)
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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: SCV000748638.5
First in ClinVar: May 21, 2018 Last updated: Aug 13, 2023 |
Comment:
Observed in the heterozygous state, sometimes using alternate nomenclature (c.1095_1098dupAATT, c.1094_1095insAATT, or c.1100_1100C>ATTAC), in multiple individuals with cancer, including breast cancer, head and neck squamous … (more)
Observed in the heterozygous state, sometimes using alternate nomenclature (c.1095_1098dupAATT, c.1094_1095insAATT, or c.1100_1100C>ATTAC), in multiple individuals with cancer, including breast cancer, head and neck squamous cell carcinoma, childhood-onset solid tumors, and lung adenocarcinoma (Akbari et al., 2011; Ellingson et al., 2015; Lhota et al., 2016; Parsons et al., 2016; Tedaldi et al., 2017; Chandrasekharappa et al., 2017; Ghazani et al., 2017); Frameshift variant predicted to result in protein truncation as the last 9 amino acids are replaced with 12 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19405097, 27506598, 26822237, 28125075, 26822949, 27659787, 28423363, 28678401, 26296701, 30306255, 32235514, 27153395, 33504652, 34585473, 35929646, 21279724, 36268089, 34308104, 36135330) (less)
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Likely benign
(Feb 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: SCV000608939.29
First in ClinVar: Oct 30, 2017 Last updated: Aug 04, 2024 |
Comment:
FANCL: BS2; VRK2: BS2
Number of individuals with the variant: 16
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Pathogenic
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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FANCONI ANEMIA, COMPLEMENTATION GROUP L
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044971.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 29, 2015 |
Comment on evidence:
For discussion of the 4-bp duplication in the FANCL gene (1095_1098dupAATT) that was found in compound heterozygous state in a patient with Fanconi anemia of … (more)
For discussion of the 4-bp duplication in the FANCL gene (1095_1098dupAATT) that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group L (FANCL; 614083) by Ali et al. (2009), see 608111.0002. (less)
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Likely pathogenic
(Jul 20, 2019)
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no assertion criteria provided
Method: curation
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Fanconi anemia complementation group L
Affected status: no
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001365354.1
First in ClinVar: Jun 28, 2020 Last updated: Jun 28, 2020 |
Comment:
Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Zdenek Kleibl.
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800208.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806996.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953664.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973305.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Feb 24, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331723.3
First in ClinVar: Dec 06, 2016 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus. | Sy MR | American journal of medical genetics. Part A | 2022 | PMID: 36135330 |
Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients. | Del Valle J | Cancers | 2020 | PMID: 32235514 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50. | Chandrasekharappa SC | Cancer | 2017 | PMID: 28678401 |
Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer. | Tedaldi G | Oncotarget | 2017 | PMID: 28423363 |
Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. | Ghazani AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125075 |
Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients. | Lhota F | Clinical genetics | 2016 | PMID: 26822949 |
Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. | Parsons DW | JAMA oncology | 2016 | PMID: 26822237 |
Mutations in Fanconi anemia genes and the risk of esophageal cancer. | Akbari MR | Human genetics | 2011 | PMID: 21279724 |
Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group. | Ali AM | Human mutation | 2009 | PMID: 19405097 |
Text-mined citations for rs759217526 ...
HelpRecord last updated Sep 01, 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.