Submissions for variant NM_000124.4(ERCC6):c.1996C>T (p.Arg666Cys)

gnomAD frequency: 0.00179  dbSNP: rs61760163

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000170374	SCV000222789	uncertain significance	not specified	2014-01-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724215	SCV000224776	uncertain significance	not provided	2018-04-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000170374	SCV000247316	uncertain significance	not specified	2014-06-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000384253	SCV000362904	likely benign	Macular degeneration	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000289884	SCV000362905	likely benign	COFS syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000344840	SCV000362906	likely benign	Cockayne syndrome	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724215	SCV000572239	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Observed in individuals with colorectal or other cancer (PMID: 28051113, 28050010, 29602769); Reported previously as a likely pathogenic variant in patients with primary ovarian insufficiency (PMID: 36099812); 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: 29784668, 28051113, 29602769, 28050010, 30653986, 34513715, 36099812)
Fulgent Genetics, Fulgent Genetics	RCV000515272	SCV000611388	uncertain significance	DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2; Lung carcinoma; UV-sensitive syndrome 1; Age related macular degeneration 5; Premature ovarian failure 11	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724215	SCV001012455	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000724215	SCV001714949	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515214	SCV003720000	likely benign	Inborn genetic diseases	2022-01-12	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.
CeGaT Center for Human Genetics Tuebingen	RCV000724215	SCV004127663	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ERCC6: PP3, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724215	SCV001548968	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ERCC6 p.Arg666Cys variant was identified in the literature in 1 of 28 proband chromosomes (frequency: 0.036) from individuals with a positive history of cancer (proband had colon cancer) (Castellanos_2017_PMID:28051113). The variant was identified in dbSNP (ID: rs61760163), LOVD 3.0 and ClinVar (classified as likely benign by Invitae and Illumina, and as uncertain significance by Claritas Genomics, Genetic Services Laboratory University of Chicago, Fulgent Genetics, EGL Genetic Diagnostics and GeneDx). The variant was identified in control databases in 498 of 282720 chromosomes (1 homozygous) at a frequency of 0.001761 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 103 of 35438 chromosomes (freq: 0.002906), Other in 20 of 7220 chromosomes (freq: 0.00277), European (non-Finnish) in 318 of 129064 chromosomes (freq: 0.002464), Ashkenazi Jewish in 22 of 10368 chromosomes (freq: 0.002122), African in 16 of 24964 chromosomes (freq: 0.000641), European (Finnish) in 16 of 25116 chromosomes (freq: 0.000637) and South Asian in 3 of 30614 chromosomes (freq: 0.000098), but was not observed in the East Asian population. The p.Arg666 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000724215	SCV001798593	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724215	SCV001963573	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724215	SCV001964569	uncertain significance	not provided		no assertion criteria provided	clinical testing