ClinVar Genomic variation as it relates to human health

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.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 19 of the ERCC5 protein (p.Pro19Leu). This variant is present in population databases (rs34291397, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ERCC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 134159). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30086788, 29641532, 27498913, 28137924, 24728327, 31937788, 30306255, 33821390)

ERCC5: BP4

Variant summary: ERCC5 c.56C>T (p.Pro19Leu) results in a non-conservative amino acid change located in the XPG, N-terminal domain (IPR006085) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 249366 control chromosomes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC5 causing Xeroderma Pigmentosum phenotype (0.00019). c.56C>T has been reported in the literature in several cancer cohorts (e.g., dosSantos_2022) and in a cohort of children with various rare genetic diseases (e.g., Chirita-Emandi_2020), but has not been reported in any individuals clearly affected with Xeroderma Pigmentosum to our knowledge. These reports therefore do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31937788, 32573973, 36077770). ClinVar contains an entry for this variant (Variation ID: 134159). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

The c.56C>T (p.P19L) alteration is located in exon 1 (coding exon 1) of the ERCC5 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the proline (P) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.