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

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001855003.5

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

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

Genes:

VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]
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

Recent activity

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DNA (cytosine-5-)-methyltransferase 1, isoform CRA_c [Rattus norvegicus]
DNA (cytosine-5-)-methyltransferase 1, isoform CRA_c [Rattus norvegicus]
gi|149020536|gb|EDL78341.1||gnl|WGS |rCP12866

Protein
FM117087 etnohea Rattus norvegicus cDNA clone etnoheaP0037C13 5', mRNA sequence
FM117087 etnohea Rattus norvegicus cDNA clone etnoheaP0037C13 5', mRNA sequence
gi|207920494|gnl|dbEST|61329144|emb 7087.1|

Nucleotide
unnamed protein product [Rattus norvegicus]
unnamed protein product [Rattus norvegicus]
gi|300591419|emb|CBV30829.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002317618	Labcorp Genetics (formerly Invitae), Labcorp	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
SCV005380902	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26633542, 34327028, 38502138 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002317618

Labcorp Genetics (formerly Invitae), Labcorp

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]

SCV005380902

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 19, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005380902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: FANCD2 c.2605+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of FANCD2 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250564 control chromosomes. c.2605+1G>A has been reported in the literature in individuals affected with features of Fanconi Anemia, including at least one homozygote (e.g., Retterer_2016, AlJabri_2021, Kunisetty_2024). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34327028, 38502138, 26633542). ClinVar contains an entry for this variant (Variation ID: 265138). Based on the evidence outlined above, the variant was 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: Oct 26, 2024

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