Submissions for variant NM_005236.3(ERCC4):c.2117T>C (p.Ile706Thr)

gnomAD frequency: 0.00190  dbSNP: rs1800069

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463526	SCV000548331	benign	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2024-01-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120815	SCV000594575	uncertain significance	not specified	2016-12-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121237	SCV001279806	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV001332584	SCV001524956	uncertain significance	XFE progeroid syndrome	2019-05-09	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	RCV001354835	SCV002009702	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001788036	SCV002030259	uncertain significance	Fanconi anemia complementation group Q	2021-03-03	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001788036	SCV002032318	uncertain significance	Fanconi anemia complementation group Q	2022-09-09	criteria provided, single submitter	clinical testing	The ERCC4 c.2117T>C (p.Ile706Thr) missense change has a maximum subpopulation frequency of 0.24% 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 ataxia (PMID: 31692161), 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.
Sema4, Sema4	RCV002257430	SCV002537939	likely benign	Xeroderma pigmentosum	2020-11-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120815	SCV002548370	benign	not specified	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: ERCC4 c.2117T>C (p.Ile706Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002515860	SCV003706955	likely benign	Inborn genetic diseases	2021-10-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003915202	SCV004745559	likely benign	ERCC4-related disorder	2022-02-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000120815	SCV000084980	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354835	SCV001549546	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ERCC4 p.Ile706Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs1800069), LOVD 3.0 and ClinVar (classified as uncertain significance by Genetic Services Laboratory, University of Chicage, and as likely benign by Invitae). The variant was identified in control databases in 366 of 268308 chromosomes (1 homozygous) at a frequency of 0.001364 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: European (non-Finnish) in 283 of 118142 chromosomes (freq: 0.002395), Other in 12 of 6702 chromosomes (freq: 0.001791), Latino in 50 of 35108 chromosomes (freq: 0.001424), European (Finnish) in 11 of 25108 chromosomes (freq: 0.000438), African in 9 of 23614 chromosomes (freq: 0.000381) and Ashkenazi Jewish in 1 of 9858 chromosomes (freq: 0.000101), but was not observed in the East Asian or South Asian populations. The p.Ile706 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. 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.