Submissions for variant NM_005236.3(ERCC4):c.16C>T (p.Pro6Ser)

gnomAD frequency: 0.00056  dbSNP: rs61760160

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475143	SCV000548330	uncertain significance	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2024-01-18	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000734582	SCV000862735	uncertain significance	not provided	2018-08-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000989531	SCV001139951	uncertain significance	Xeroderma pigmentosum, group F	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000734582	SCV001150808	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000989531	SCV001279552	uncertain significance	Xeroderma pigmentosum, group F	2017-04-27	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001292633	SCV001481225	uncertain significance	Fanconi anemia complementation group Q	2020-01-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000734582	SCV002009707	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000734582	SCV002107215	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	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)
Sema4, Sema4	RCV002257426	SCV002537732	uncertain significance	Xeroderma pigmentosum	2021-09-15	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001292633	SCV002584654	uncertain significance	Fanconi anemia complementation group Q	2022-09-22	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002477311	SCV002796336	uncertain significance	Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q	2022-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120803	SCV003844912	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV004019681	SCV004865257	uncertain significance	Inborn genetic diseases	2022-07-04	criteria provided, single submitter	clinical testing	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.
Breakthrough Genomics, Breakthrough Genomics	RCV000734582	SCV005194234	uncertain significance	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120803	SCV000084967	not provided	not specified	2013-09-19	no assertion provided	reference population
Genetic Services Laboratory, University of Chicago	RCV000120803	SCV003839479	uncertain significance	not specified	2022-08-18	no assertion criteria provided	clinical testing	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.