NM_018062.4(FANCL):c.223C>T (p.Gln75Ter) AND Fanconi anemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 18, 2023
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:: RCV002282910.3

Allele description [Variation Report for NM_018062.4(FANCL):c.223C>T (p.Gln75Ter)]

NM_018062.4(FANCL):c.223C>T (p.Gln75Ter)

Gene:

FANCL:FA complementation group L [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p16.1

Genomic location:

Preferred name:

NM_018062.4(FANCL):c.223C>T (p.Gln75Ter)

HGVS:

NC_000002.12:g.58226778G>A
NG_007418.1:g.19602C>T
NM_001114636.2:c.223C>T
NM_001374615.1:c.223C>T
NM_001410792.1:c.223C>T
NM_018062.4:c.223C>TMANE SELECT
NP_001108108.1:p.Gln75Ter
NP_001108108.1:p.Gln75Ter
NP_001361544.1:p.Gln75Ter
NP_001397721.1:p.Gln75Ter
NP_060532.2:p.Gln75Ter
NP_060532.2:p.Gln75Ter
LRG_501t1:c.223C>T
LRG_501t2:c.223C>T
LRG_501:g.19602C>T
LRG_501p1:p.Gln75Ter
LRG_501p2:p.Gln75Ter
NC_000002.11:g.58453913G>A
NM_001114636.1:c.223C>T
NM_018062.3:c.223C>T
NR_164659.1:n.217C>T
NR_164659.2:n.235C>T

Protein change:

Q75*

Molecular consequence:

NM_001114636.2:c.223C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374615.1:c.223C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001410792.1:c.223C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018062.4:c.223C>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
SCV002570905	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004276616	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19405097, 23613520, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002570905

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 15, 2022)

germline

clinical testing

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

Citation Link,

SCV004276616

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 18, 2023)

germline

clinical testing

PubMed (3)
[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

Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer.

Tedaldi G, Tebaldi M, Zampiga V, Danesi R, Arcangeli V, Ravegnani M, Cangini I, Pirini F, Petracci E, Rocca A, Falcini F, Amadori D, Calistri D.

Oncotarget. 2017 Jul 18;8(29):47064-47075. doi: 10.18632/oncotarget.16791.

PubMed [citation]

PMID:: 28423363
PMCID:: PMC5564544

Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.

Ali AM, Kirby M, Jansen M, Lach FP, Schulte J, Singh TR, Batish SD, Auerbach AD, Williams DA, Meetei AR.

Hum Mutat. 2009 Jul;30(7):E761-70. doi: 10.1002/humu.21032.

PubMed [citation]

PMID:: 19405097
PMCID:: PMC2760491

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570905.1

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

Description

Variant summary: FANCL c.223C>T (p.Gln75X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g. c.739_740dup (p.Met247fs), c.296_297del (p.Gln99fs)). The variant was absent in 251050 control chromosomes (gnomAD). Although c.223C>T has not been reported in the literature in individuals affected with Fanconi Anemia, it has been found in a setting of multigene panel testing in at least one individual with breast cancer (e.g. Tedaldi_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004276616.1

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

Description

This sequence change creates a premature translational stop signal (p.Gln75*) in the FANCL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCL are known to be pathogenic (PMID: 19405097, 23613520). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FANCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1704583). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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: Sep 29, 2024

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