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NM_000135.4(FANCA):c.2602-13CT[2] AND Fanconi anemia

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1); Uncertain significance(2); Benign(1) (Last evaluated: Dec 12, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000227314.17

Allele description [Variation Report for NM_000135.4(FANCA):c.2602-13CT[2]]

NM_000135.4(FANCA):c.2602-13CT[2]

Gene:
FANCA:FA complementation group A [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_000135.4(FANCA):c.2602-13CT[2]
HGVS:
  • NC_000016.10:g.89765074AG[2]
  • NG_011706.1:g.56579CT[2]
  • NM_000135.4:c.2602-13CT[2]MANE SELECT
  • NM_001286167.3:c.2602-13CT[2]
  • LRG_495t1:c.2602-9_2602-8del
  • LRG_495:g.56579CT[2]
  • NC_000016.9:g.89831482AG[2]
  • NC_000016.9:g.89831482_89831483del
  • NM_000135.2:c.2602-9_2602-8del
  • NM_000135.2:c.2602-9_2602-8delCT
  • NM_000135.3:c.2602-9_2602-8del
  • NM_000135.4:c.2602-9_2602-8delCTMANE SELECT
Links:
dbSNP: rs577636020
NCBI 1000 Genomes Browser:
rs577636020
Molecular consequence:
  • NM_000135.4:c.2602-13CT[2] - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001286167.3:c.2602-13CT[2] - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Fanconi anemia (FA)
Synonyms:
Fanconi pancytopenia; Fanconi's anemia
Identifiers:
MONDO: MONDO:0019391; MeSH: D005199; MedGen: C0015625; Orphanet: 84; OMIM: PS227650

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000283553Invitaecriteria provided, single submitter
Benign
(Dec 12, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000399839Illumina Laboratory Services,Illuminacriteria provided, single submitter
Uncertain significance
(Jun 14, 2016)
germlineclinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV001821391Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Aug 26, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV002032315St. Jude Molecular Pathology, St. Jude Children's Research Hospitalcriteria provided, single submitter
Uncertain significance
(Dec 9, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.

Bonache S, Esteban I, Moles-Fernández A, Tenés A, Duran-Lozano L, Montalban G, Bach V, Carrasco E, Gadea N, López-Fernández A, Torres-Esquius S, Mancuso F, Caratú G, Vivancos A, Tuset N, Balmaña J, Gutiérrez-Enríquez S, Diez O.

J Cancer Res Clin Oncol. 2018 Dec;144(12):2495-2513. doi: 10.1007/s00432-018-2763-9. Epub 2018 Oct 10.

PubMed [citation]
PMID:
30306255
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000283553.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services,Illumina, SCV000399839.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821391.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: FANCA c.2602-9_2602-8delCT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, the variant has been shown to cause aberrant splicing in a patient derived cell line carrying the variant (Kimble_2018). The variant allele was found at a frequency of 0.00071 in 251154 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FANCA causing Fanconi Anemia (0.00071 vs 0.0022), allowing no conclusion about variant significance. c.2602-9_2602-8delCT has been reported in the literature in individuals affected with Fanconi Anemia (Kimble_2018) and also in breast cancer patients (Bonache_2018, DelValle_2020, Schubert_2019). These data indicate that the variant may be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely pathogenic (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002032315.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 21, 2023

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