Submissions for variant NM_000122.2(ERCC3):c.847C>T (p.Arg283Cys)

gnomAD frequency: 0.00146  dbSNP: rs145201970

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000120800	SCV000257629	uncertain significance	not specified	2015-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765502	SCV000896805	uncertain significance	Xeroderma pigmentosum group B; Trichothiodystrophy 2, photosensitive	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129472	SCV001289000	uncertain significance	Xeroderma pigmentosum group B	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics	RCV001294157	SCV001482982	uncertain significance	Trichothiodystrophy 2, photosensitive	2019-10-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001362006	SCV001558002	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 283 of the ERCC3 protein (p.Arg283Cys). This variant is present in population databases (rs145201970, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma and prostate cancer (PMID: 28259476, 30414346). ClinVar contains an entry for this variant (Variation ID: 134128). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC3 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001362006	SCV002010233	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001362006	SCV002097482	uncertain significance	not provided	2022-02-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and family history of melanoma or breast cancer (Bonache 2018, Potjer 2019); This variant is associated with the following publications: (PMID: 24728327, 30306255, 30414346)
Sema4, Sema4	RCV002257425	SCV002532641	uncertain significance	Xeroderma pigmentosum	2021-10-28	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120800	SCV003844755	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: ERCC3 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 251462 control chromosomes (gnomAD). The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC3 causing Xeroderma Pigmentosum phenotype (0.00011), strongly suggesting that the variant could be benign. c.847C>T has been reported in the literature in individuals as not co-segregating with the melanoma phenotype in two affected members from at least one family (Potjer_2019). It has additionally been reported in individuals affected with breast cancer (Bonache_2018, VanMarke_2020) and prostate cancer (Mateo_2020) as well as an individual from a cohort of healthy controls (n=681) (Bodian_2014). Since the penetrance of Xeroderma Pigmentosum due to this variant appears to be lower than expected, no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 30306255, 31874108, 31664448, 30414346, 32295625). Eight ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004019680	SCV004865254	likely benign	Inborn genetic diseases	2021-11-19	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.
ITMI	RCV000120800	SCV000084964	not provided	not specified	2013-09-19	no assertion provided	reference population