Confirmed Fanconi anaemia or Bloom syndrome

Gene: XRCC2

Green List (high evidence)

Comment on list classification: There are now 3 unrelated individuals with biallelic XRCC2 variants and Fanconi anaemia. All reported patients were homozygous for a recurrent p.(Arg215Ter) variant. Functional evidence is supportive of this gene-disease association. Hence, this gene should be promoted at the next GMS update.

Created: 8 May 2026, 3:20 p.m. | Last Modified: 8 May 2026, 3:20 p.m.

Panel Version: 2.14

PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with AR Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.

Created: 8 May 2026, 3:11 p.m. | Last Modified: 8 May 2026, 3:25 p.m.

Panel Version: 2.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Fanconi anemia, complementation group U, OMIM:617247

Publications

• 42071175

Comment on list classification: Single FA-U patient in literature at present but with supportive functional data. Additional published cases required to confirm pathogenicity and support inclusion of XRCC2 on a diagnostic FA panel.

Created: 2 Dec 2020, 3:31 p.m. | Last Modified: 2 Dec 2020, 3:31 p.m.

Panel Version: 1.9

Green List (high evidence)

NM_005431.1:c.643C>T p.(Arg215*) identified in Shamseldin et al 2012 by exome sequencing in a patient with a phenotype consistent with Fanconi anaemia. XRCC2 knockout shown to be embryonic lethal in mice with phenotype consistent with FA and functions in RAD51 homologous recombination pathway (Shamseldin and references therein). Park et al 2016 showed phenotypic rescue of XRCC2-deficient cell lines. Additional patient identified by North Thames GMC (referred by clinical genetics, Glasgow), phenotype consistent with FA (hypoplastic thumbs, microcephaly, renal anomalies, spinal anomaly) and has a ~14Mb region of LOH at 7q34-q36.2 encompassing the XRCC2 gene. Mitomycin breakage studies inconclusive on two occasions (limited increase in breakage). Same c.643C>T p.(Arg215*) truncating variant identified, apparently homozygous.

Created: 7 Apr 2020, 1:46 p.m. | Last Modified: 7 Apr 2020, 1:46 p.m.

Panel Version: 1.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Fanconi anaemia complementation group U

Publications

• PMID: 22232082
• 27208205

I don't know

Initial gene list (Consensus Genes for Panels_Haem_SHEFFIELD-29.01.2019.xlsx) collated by Mandy Nesbitt Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Trust January 2019 on behalf of Yorkshire and North East GLH for the GMS Haematology specialist test group. Gene Symbol submitted: XRCC2; Suggested intial gene rating: I don't know; Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Phenotypes: 617247 ?Fanconi anemia, complementation group U; PMID(s): none submitted

Created: 14 Feb 2019, 4:52 p.m.

Red List (low evidence)

Gene rating submitted by Mandy Nesbitt SheffieldDiagnostic Genetics Service, Sheffield Children's NHS Trust January 2019 on behalf of Yorkshire and North EastGLH for the GMS Haematology specialist test group.

Created: 14 Feb 2019, 4:48 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
617247 ?Fanconi anemia, complementation group U