NM_001018115.3(FANCD2):c.757C>T (p.Arg253Ter) AND Fanconi anemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 17, 2023
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:: RCV000808868.9

Allele description [Variation Report for NM_001018115.3(FANCD2):c.757C>T (p.Arg253Ter)]

NM_001018115.3(FANCD2):c.757C>T (p.Arg253Ter)

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.757C>T (p.Arg253Ter)

HGVS:

NC_000003.12:g.10041684C>T
NG_007311.1:g.20256C>T
NG_046754.1:g.10838C>T
NM_001018115.3:c.757C>TMANE SELECT
NM_001319984.2:c.757C>T
NM_001374253.1:c.757C>T
NM_001374254.1:c.757C>T
NM_033084.6:c.757C>T
NP_001018125.1:p.Arg253Ter
NP_001306913.1:p.Arg253Ter
NP_001361182.1:p.Arg253Ter
NP_001361183.1:p.Arg253Ter
NP_149075.2:p.Arg253Ter
LRG_306t1:c.757C>T
LRG_306t2:c.757C>T
LRG_306:g.20256C>T
NC_000003.11:g.10083368C>T
NM_001018115.1:c.757C>T
NM_033084.3:c.757C>T

Protein change:

R253*

Links:

dbSNP: rs374328858

NCBI 1000 Genomes Browser:

rs374328858

Molecular consequence:

NM_001018115.3:c.757C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001319984.2:c.757C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374253.1:c.757C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374254.1:c.757C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033084.6:c.757C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000948996	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17436244, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000948996

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 17, 2023)

germline

clinical testing

PubMed (2)
[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

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

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

Details of each submission

From Invitae, SCV000948996.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg253*) in the FANCD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCD2 are known to be pathogenic (PMID: 17436244). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 653154). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 17436244). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs374328858, gnomAD 0.004%).

#	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 15, 2024

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