ClinVar Genomic variation as it relates to human health

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

Variant summary: ERCC4 c.16C>T (p.Pro6Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 242132 control chromosomes. The observed variant frequency is approximately 2.37 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), suggesting that the variant may be benign. However no homozygous control individuals were observed. c.16C>T has been reported in the literature in at least one heterozygous individual affected with familial early-onset skin cancer without evidence of cosegregation (e.g. Matakidou_2006). These report(s) 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. Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, all classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.16C>T (p.P6S) alteration is located in exon 1 (coding exon 1) of the ERCC4 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the proline (P) at amino acid position 6 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The ERCC4 c.16C>T (p.Pro6Ser) missense change has a maximum subpopulation frequency of 0.093% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with a personal and/or family history of lung cancer (PMID: 16550608) and breast cancer (PMID: 27153395). To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, or lung cancer (Matakidou 2006, Maxwell 2016); This variant is associated with the following publications: (PMID: 24728327, 16550608, 27153395)

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the ERCC4 protein (p.Pro6Ser). This variant is present in population databases (rs61760160, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lung cancer (PMID: 16550608). ClinVar contains an entry for this variant (Variation ID: 134131). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.16C>T, in exon 1 that results in an amino acid change, p.Pro6Ser. This sequence change has been previously described in individuals with lung cancer (PMID: 16550608) and breast and/or ovarian cancer (PMID: 27153395). This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European subpopulation (dbSNP rs61760160). The p.Pro6Ser change affects a poorly conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Pro6Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro6Ser change remains unknown at this time.