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NM_006296.7(VRK2):c.*102_*105dup AND not specified

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Feb 22, 2022
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000192919.13

Allele description [Variation Report for NM_006296.7(VRK2):c.*102_*105dup]

NM_006296.7(VRK2):c.*102_*105dup

Genes:
FANCL:FA complementation group L [Gene - OMIM - HGNC]
VRK2:VRK serine/threonine kinase 2 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2p16.1
Genomic location:
Preferred name:
NM_006296.7(VRK2):c.*102_*105dup
HGVS:
  • NC_000002.11:g.58386929_58386932dup
  • NC_000002.12:g.58159795_58159798dup
  • NG_007418.1:g.86583_86586dup
  • NG_029717.2:g.257055_257058dup
  • NM_001114636.2:c.1110_1113dup
  • NM_001130480.2:c.*102_*105dup
  • NM_001130481.2:c.*102_*105dup
  • NM_001130482.2:c.*102_*105dup
  • NM_001130483.2:c.*487_*490dup
  • NM_001288836.1:c.*102_*105dup
  • NM_001288837.2:c.*102_*105dup
  • NM_001288838.2:c.*487_*490dup
  • NM_001288839.2:c.*102_*105dup
  • NM_001374615.1:c.1141_1144dup
  • NM_001410792.1:c.1156_1159dup
  • NM_006296.7:c.*102_*105dupMANE SELECT
  • NM_018062.4:c.1096_1099dupMANE SELECT
  • NP_001108108.1:p.Thr372Asnfs
  • NP_001108108.1:p.Thr372fs
  • NP_001361544.1:p.Thr382fs
  • NP_001397721.1:p.Thr387fs
  • NP_060532.2:p.Thr367Asnfs
  • NP_060532.2:p.Thr367fs
  • LRG_501t1:c.1111_1114dup
  • LRG_501t2:c.1095_1098dup
  • LRG_501:g.86583_86586dup
  • LRG_501p1:p.Thr372fs
  • LRG_501p2:p.Thr367Asnfs
  • NC_000002.11:g.58386928_58386929insTAAT
  • NC_000002.11:g.58386929_58386932dup
  • NC_000002.11:g.58386930_58386933dup
  • NM_001114636.1:c.1111_1114dup
  • NM_001114636.1:c.1111_1114dupATTA
  • NM_018062.3:c.1095_1098dup
  • NM_018062.3:c.1096_1099dupATTA
  • NM_018062.4:c.1096_1099dup
  • NR_156742.1:n.885_888dup
  • NR_156742.2:n.829_832dup
  • NR_164659.1:n.977_980dup
  • NR_164659.2:n.994_997dup
Protein change:
T367fs
Links:
LOVD 3: FANCL_000003; OMIM: 608111.0003; dbSNP: rs759217526
NCBI 1000 Genomes Browser:
rs759217526
Molecular consequence:
  • NM_001130480.2:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001130481.2:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001130482.2:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001130483.2:c.*487_*490dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001288836.1:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001288837.2:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001288838.2:c.*487_*490dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001288839.2:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_006296.7:c.*102_*105dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001114636.2:c.1110_1113dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001374615.1:c.1141_1144dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001410792.1:c.1156_1159dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_018062.4:c.1096_1099dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000247355Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Aug 2, 2019) 		germlineclinical testing

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

SCV002103929Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Benign
(Feb 22, 2022) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000247355.2

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002103929.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

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

Last Updated: Oct 8, 2024