ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27655433 A truncating mutation c.325C>T:p.Arg109* (R109X) in exon 3 of ERCC3 was observed recurrently among exomes sequenced in BRCA negative, breast cancer-affected individuals of Ashkenazi Jewish ancestry. It was detected in three affected siblings from a family with multiple cancer affecters. The same variant was observed in two other individuals from an unrelated family with multiple cases of breast cancer. Modeling of the mutation in ERCC3 deficient or CRISPR/Cas9 edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6500 chromosomes of breast cancer cases and 6800 Ashkenazi controls showed significant association with breast cancer risk (ORBC=1.53, ORER+=1.73) particularly for the estrogen receptor positive (ER+) subset (P<0.007). However, the variant was observed in the gnomAD with a minor allele frequency of 0.92% (95/10370, 0 hom) in the Ashkenazi Jewish subpopulation. The MAFs in male and female in the overall population are similar (~0.49%).
28202063 Jalkh et al performed whole exome sequencing in 45 patients with a reported family history of breast cancer and identified a rare nonsense variant in exon 6 of ERCC3 (NM_000122.1): c.700C>T p.R234* in the family 3/patient B22 who was also found to carry multiple variants in different cancer predisposition genes (eg. BRCA2, TP53, VHL PTCH1); however, none of these variants can be classified as pathogenic or likely pathogenic. No segregation data is available. The association between ERCC3 and breast cancer cannot be established based on this study.

Haploinsufficiency phenotype comments:

Biallelic disease-causing variants in ERCC3 can cause autosomal recessive disorders Trichothiodystrophy 2, photosensitive (TTD) or Xeroderma pigmentosum, group B. Oh et al (2006) reported multiple patients from six families with biallelic disease-causing variants in the ERCC3 gene. Clinical features in these patients include Xeroderma Pigmentosum type B (XPB) with or without Cockayne syndrome and Trichothiodystrophy 2 (TTD). Functional assessment of patient-derived cells suggested all XPB cells had reduced nucleotide excision repair (NER) and post-UV cell viability. Cells from patients with missense variants displayed different levels of DNA repair and clinical features. Some missense variants produced a much less severe reduction of NER. They concluded that the remarkable phenotypic heterogeneity of XPB among these families was associated with different genotypes. Patients with milder phenotype carry partially active missense variants in one allele and a truncating variant in the other allele while severe patients have truncating variants in both alleles resulting in low levels of altered XPB protein. No symptoms were reported in parents or siblings who carry a heterozygous variant [PMID: 16947863]. Heterozygous truncating variants were reported in multiple individuals with different types of cancers including breast cancer, colorectal carcinoma, medulloblastoma et al, however, the evidence for this association is limited.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence to support the triplosensitivity of this gene.