NM_001018115.3(FANCD2):c.2605+1G>A AND Fanconi anemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 18, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001855003.3

Allele description [Variation Report for NM_001018115.3(FANCD2):c.2605+1G>A]

NM_001018115.3(FANCD2):c.2605+1G>A

Genes:

LOC107303338:3p25 FANCD2 Alu-mediated recombination region [Gene]
FANCD2:FA complementation group D2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_001018115.3(FANCD2):c.2605+1G>A

HGVS:

NC_000003.12:g.10072982G>A
NG_007311.1:g.51554G>A
NG_046754.1:g.42136G>A
NM_001018115.3:c.2605+1G>AMANE SELECT
NM_001319984.2:c.2605+1G>A
NM_001374253.1:c.2494+1G>A
NM_001374254.1:c.2605+1G>A
NM_033084.6:c.2605+1G>A
LRG_306t2:c.2605+1G>A
LRG_306:g.51554G>A
NC_000003.11:g.10114666G>A
NM_033084.3:c.2605+1G>A
NM_033084.5:c.2605+1G>A

Links:

dbSNP: rs142365855

NCBI 1000 Genomes Browser:

rs142365855

Molecular consequence:

NM_001018115.3:c.2605+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001319984.2:c.2605+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001374253.1:c.2494+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001374254.1:c.2605+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_033084.6:c.2605+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002317618	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 17436244, 26633542, 34327028, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002317618

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype.

Kalb R, Neveling K, Hoehn H, Schneider H, Linka Y, Batish SD, Hunt C, Berwick M, Callen E, Surralles J, Casado JA, Bueren J, Dasi A, Soulier J, Gluckman E, Zwaan CM, van Spaendonk R, Pals G, de Winter JP, Joenje H, Grompe M, Auerbach AD, et al.

Am J Hum Genet. 2007 May;80(5):895-910. Epub 2007 Apr 6. Erratum in: Am J Hum Genet. 2007 Jul;81(1):196.

PubMed [citation]

PMID:: 17436244
PMCID:: PMC1852747

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002317618.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 27 of the FANCD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCD2 are known to be pathogenic (PMID: 17436244). This variant is present in population databases (rs142365855, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 26633542, 34327028). ClinVar contains an entry for this variant (Variation ID: 265138). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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