Submissions for variant NM_000400.4(ERCC2):c.1774C>T (p.Arg592Cys)

gnomAD frequency: 0.00002  dbSNP: rs190678702

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001131691	SCV001291322	uncertain significance	Xeroderma pigmentosum, group D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235477	SCV003934493	uncertain significance	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: ERCC2 c.1774C>T (p.Arg592Cys) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251212 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1774C>T has been reported in the literature as an uninformative genotype (i.e. zygosity not specified) in an individual with CNS medulloblastoma (Kim_2021), however to our knowledge it has not been reported in individuals affected with Xeroderma Pigmentosum. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant exhibited reduced growth rates under DNA-damaging conditions in a yeast model system, however, this study does not allow convincing conclusions about the variant effect (Kim_2018). The following publications have been ascertained in the context of this evaluation (PMID: 34308104, 29522548). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.