Submissions for variant NM_000400.4(ERCC2):c.[1381C>G;2150C>G]

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003123387	SCV003800758	pathogenic	Xeroderma pigmentosum	2023-01-04	criteria provided, single submitter	clinical testing	Variant summary: ERCC2 c.[1381C>G;2150C>G] (p.[Leu461Val;Ala717Gly]) variant is a complex allele and involves the alteration of multiple nucleotides. These two variants have always been reported in cis in the literature. At least one publication reports experimental evidence that this complex allele variant affects mRNA splicing, although the evidence is primarily driven by the component c.2150C>G. Several computational tools predict a significant impact on normal splicing: Four predict the c.2150C>G strengthens a cryptic exonic 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in splicing-out of the last 45 bases of exon 22 resulting in r.[1381c>g;2146_2190del], which is translated into p.[L461V;V716_R730del] (Horibata_2015). Based on the frequency of c.2150C>G, this complex allele variant allele was found at a frequency not to exceed 0.00031 in 251244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum/Trichothiodystrophy (0.00031 vs 0.00061), allowing no conclusion about variant significance. c.[1381C>G;2150C>G] has been reported in the literature always a complex allele in compound heterozygous genotypes with other pathogenic alleles in multiple individuals with features of Xeroderma Pigmentosum and Trichothiodystrophy (example, Takayama_1996, Moslehi_2012, Fujimoto_2005, Zhou_2013, Fassihi_2016, Horibata_2015). This complex allele has also been reported in individuals with various cancers, although these findings have not been ascertained in the context of this evaluation. These data indicate that the variant in its complex allele configuration is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact of the complex allele on protein function (example, Horibata_2015). The most pronounced variant effect abolishes the helicase, Nucleotide Excision Repair (NER) activity and the transcriptional activity of TFIIH. However, although individually, p.Leu461Val and p.Ala717Gly possessed full NER activity (comparable to p.WT), the combined mutant p.[Leu461Val; Ala717Gly] possessed only partial NER activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this complex allele variant to ClinVar after 2014. Based on the evidence outlined above, this complex allele variant was classified as pathogenic.