Submissions for variant NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr)

gnomAD frequency: 0.00082  dbSNP: rs1800068

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651477	SCV000773329	likely benign	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001119237	SCV001277596	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	RCV001294105	SCV001482918	uncertain significance	Fanconi anemia complementation group Q	2019-09-26	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	RCV001357601	SCV002009706	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001294105	SCV002032317	uncertain significance	Fanconi anemia complementation group Q	2022-08-17	criteria provided, single submitter	clinical testing	The ERCC4 c.1727G>C (p.Arg576Thr) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 32008151, 34117267), head and neck squamous cell carcinoma (PMID: 28678401), and pancreatic ductal adenocarcinoma (PMID: 28767289). 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.
Genetic Services Laboratory, University of Chicago	RCV000120831	SCV002071319	uncertain significance	not specified	2021-09-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.1727G>C, in exon 8 that results in an amino acid change, p.Arg576Thr. This sequence change has been described in the gnomAD database with a frequency of 0.13% in the Latino sub-population (dbSNP rs1800068). The p.Arg576Thr change has been reported in individuals with head and neck carcinoma and pancreatic cancer (PMIDs: 28678401, 28767289). The p.Arg576Thr change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Arg576Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg576Thr change remains unknown at this time.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002055332	SCV002496110	uncertain significance	Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q	2021-07-16	criteria provided, single submitter	clinical testing	ERCC4 NM_005236.2 exon 8 p.Arg576Thr (c.1727G>C):This variant has been reported in the literature in at least 4 individuals: 1 with head/neck squamous cell carcinoma, 3 with pancreatic ductal adenocarcinoma (Chanrasekharappa 2017 PMID:28678401, Shindo 2017 PMID:28767289). This variant is present in 0.1% (29/15276) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-13935659-G-C?dataset=gnomad_r3) This variant is present in ClinVar (Variation ID:134158). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Sema4, Sema4	RCV002257433	SCV002537735	uncertain significance	Xeroderma pigmentosum	2022-01-04	criteria provided, single submitter	curation
Ambry Genetics	RCV002515863	SCV003685116	uncertain significance	Inborn genetic diseases	2021-11-16	criteria provided, single submitter	clinical testing	The c.1727G>C (p.R576T) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a G to C substitution at nucleotide position 1727, causing the arginine (R) at amino acid position 576 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
ITMI	RCV000120831	SCV000084996	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357601	SCV001553115	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ERCC4 p.Arg576Thr variant was identified in 10 of 6374 proband chromosomes (frequency: 0.001569) from individuals with breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma or head and neck squamous cell carcinoma and was present in 2 of 154 control chromosomes (frequency: 0.01299) from healthy individuals (McVeigh_2020_PMID:32008151; West_2018; Shindo_2017_PMID:28767289; Chandrasekharappa_2017_PMID:28678401). The variant was identified in dbSNP (ID: rs1800068) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 185 of 281516 chromosomes at a frequency of 0.0006572 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 45 of 35426 chromosomes (freq: 0.00127), European (non-Finnish) in 126 of 127888 chromosomes (freq: 0.000985), Other in 7 of 7216 chromosomes (freq: 0.00097), African in 5 of 24972 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25102 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg576 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional assays demonstrated defective DNA repair function after UV-induced DNA damage with ERCC4 p.R576T compared to wildtype (West_2018). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001357601	SCV001742068	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001357601	SCV001972335	uncertain significance	not provided		no assertion criteria provided	clinical testing