Submissions for variant NM_000122.2(ERCC3):c.657+1G>A

gnomAD frequency: 0.00001  dbSNP: rs56116802

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001973143	SCV002255043	likely pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1469975). Disruption of this splice site has been observed in individual(s) with thyroid carcinoma, personal and/or family history of breast and ovarian cancer (PMID: 29625052, 30262796). This variant is present in population databases (rs56116802, gnomAD 0.006%). This sequence change affects a donor splice site in intron 5 of the ERCC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002266076	SCV002547834	likely pathogenic	Xeroderma pigmentosum	2022-05-25	criteria provided, single submitter	clinical testing	Variant summary: ERCC3 c.657+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site whereas two predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251480 control chromosomes. To our knowledge c.657+1G>A has not been reported in the literature in individuals affected with Xeroderma Pigmentosum, however it has been observed in individuals with breast cancer and thyroid cancer (example Quezada Urban_2018, Huang_2018, Palmer_2020, Fasching_2021). These reports 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.