rs577636020

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000135.4(FANCA):c.2602-9_2602-8del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

FANCA
NM_000135.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7B:1

Conservation

PhyloP100: 0.996

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.2602-9_2602-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389301.8
FANCA	NM_001286167.3 linkuse as main transcript	c.2602-9_2602-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.2602-9_2602-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000135.4	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000713

AC:

179

AN:

251154

Hom.:

AF XY:

0.000707

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.000864

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000585

AC:

855

AN:

1461596

Hom.:

AF XY:

0.000589

AC XY:

428

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00103

Gnomad4 FIN exome

AF:

0.00210

Gnomad4 NFE exome

AF:

0.000532

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000434

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000654

Hom.:

Bravo

AF:

0.000400

EpiCase

AF:

0.00104

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia

Pathogenic:1Uncertain:2Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The c.2602-9_2602-8delCT variant in FANCA has been reported in two individuals with Fanconi anemia both of whom were compound heterozygous for the variant and a large deletion of FANCA on the other allele (Kimble 2018 PMID: 29098742). It has also been reported in 2 individuals with early-onset renal cell carcinoma, 1 child with neuroblastoma and a distant family history of cancer, and 2 breast cancer patients (initial diagnosis < 55 yrs for both) (Truong 2021 PMID: 34654685, Fiala 2021 PMID: 34308366, del Valle 2020 PMID: 32235514). It was also identified in 0.07% (45/68038) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 237041). RT-PCR analysis lymphoblastoid cell lines derived from one of the Fanconi anemia patients suggests that the variant results in aberrant splicing, and thus would be expected to lead to a truncated or absent protein. Loss of function of the FANCA gene is an established disease mechanism for autosomal recessive Fanconi anemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Fanconi anemia. ACMG/AMP criteria applied: PM3, PS3, PP4. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Dec 09, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2020	Variant detected in two families with Fanconi Anemia and was shown to lead to aberrant splicing by RT-PCR (Kimble 2018); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing.; This variant is associated with the following publications: (PMID: 32235514, 29098742, 25589003) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FANCA: PM3, PM2:Supporting, PS3:Supporting, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2023	In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32235514 (2020), 30306255 (2018), 30426508 (2018)), renal cell carcinoma (PMID: 34654685 (2021)), and Fanconi Anemia (PMID: 29098742 (2018)). This variant has been shown to result in aberrant splicing with skipping of exons 28-30 and exon 29 of the FANCA gene (PMID: 29098742 (2018)). The frequency of this variant in the general population, 0.00088 (113/128910 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on FANCA mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 16, 2019	DNA sequence analysis of the FANCA gene demonstrated a sequence change in intron 27, c.2602-9_2602-8del. This sequence change has been described in the gnomAD database with a frequency of 0.17% in European populations (dbSNP rs577636020). This sequence change, in addition to a large pathogenic deletion, has been identified in a Fanconi anemia family. RNA analysis of these individuals demonstrated skipping of exons 28-30 in the presence of this sequence change (PMID: 29098742). This sequence change is also predicted to have a deleterious effect on splicing based on in silico splice prediction programs. The functional significance of this sequence change is not known at present. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2023	Variant summary: FANCA c.2602-9_2602-8delCT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, the variant has been shown to cause aberrant splicing in a patient derived cell line carrying the variant (Kimble_2018). The variant allele was found at a frequency of 0.00071 in 251154 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FANCA causing Fanconi Anemia (0.00071 vs 0.0022), allowing no conclusion about variant significance. c.2602-9_2602-8delCT has been reported in the literature in individuals affected with Fanconi Anemia (Kimble_2018) and also in breast cancer patients (Bonache_2018, DelValle_2020, Schubert_2019). These reports do not provide unequivocal conclusions about the variant significance. This variant and FANCA c.1074_1075del/p.Tyr359fs (CV ID: 237032, classified pathogenic) has been observed in an unaffected adult internally. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely pathogenic (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Fanconi anemia complementation group A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Dec 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over