rs577636020

Variant names:

• chr16-89765073-CAG-C
• rs577636020
• NM_000135.4:c.2602-9_2602-8delCT

Variant summary

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

The NM_000135.4(FANCA):​c.2602-9_2602-8delCT variant causes a splice region, 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, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:9 B:1
• Conservation: PhyloP100: 0.996

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]

ACMG classification

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 rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.2602-9_2602-8delCT		splice_region_variant, intron_variant	Intron 27 of 42	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.2602-9_2602-8delCT		splice_region_variant, intron_variant	Intron 27 of 42		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.2602-9_2602-8delCT		splice_region_variant, intron_variant	Intron 27 of 42	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152240 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.000707 AC XY: 96 AN XY: 135782

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.: 0 AF XY: 0.000589 AC XY: 428 AN XY: 727090

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: 66 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74378

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.: 0

Bravo AF: 0.000400

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia Pathogenic:1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Dec 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2025	- -
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. -

Fanconi anemia complementation group A Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2024	- -

not provided Uncertain:3

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	GeneDx	Jun 25, 2024	Reported in two individuals from related families with Fanconi anemia who also have a multi-exon deletion on the opposite allele (in trans); RNA testing in one family suggests this variant leads to aberrant splicing (PMID: 29098742); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25589003, 34426522, 30426508, 34308366, 32235514, 34654685, 30306255, 29098742) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 21, 2024	The FANCA c.2602-9_2602-8del variant has been reported in the published literature 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, 0.0021 (10/4830 chromosomes in Estonian subpopulation (Genome Aggregation Database, 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. -

FANCA-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2024

The FANCA c.2602-9_2602-8delCT variant is predicted to result in an intronic deletion. This variant has been reported in two related individuals with Fanconi anemia (FA) who also harbored a partial deletion of FANCA on the opposite allele (Kimble et al. 2018. PubMed ID: 29098742). This variant has also been reported in several individuals with cancer (Bonache et al. 2018. PubMed ID: 30306255; Schubert et al. 2019. PubMed ID: 30426508; Del Valle et al. 2020. PubMed ID: 32235514; Fiala et al. 2021. PubMed ID: 34308366), although some of these individuals also have pathogenic variants in other genes associated with increased cancer risk (see Truong et al. 2021. PubMed ID: 34654685). In silico splicing prediction programs indicate that this variant weakens the adjacent canonical acceptor site (Alamut Visual Plus v1.6.1; SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and RNA analysis confirmed the presence of altered splice variants in FA patient cell lines (Kimble et al. 2018. PubMed ID: 29098742). A different study in patients with suspected hereditary cancer disorders stated that normal splicing was observed but did not provide supporting data for review (Del Valle et al. 2020. PubMed ID: 32235514). This variant is reported in 0.17% (42 of 25,108) of alleles in individuals of European (Finnish) descent in gnomAD but only occurs in 0.063% (162 of 257,444) of alleles in non-Finnish populations. Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs577636020; hg19: chr16-89831481;