Submissions for variant NM_007294.4(BRCA1):c.5153G>C (p.Trp1718Ser)

dbSNP: rs41293461

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Medical Genetics, Oslo University Hospital	RCV000112538	SCV000564371	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-04	criteria provided, single submitter	clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001269394	SCV001449164	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-16	criteria provided, single submitter	clinical testing	Data included in classification: The variant is absent from population data and has not been reported by UK laboratories. In silico prediction shows a deleterious effect. This variant does not alter splicing (Ahlborn et al 2015), but has been shown in multiple functional studies (Lee et al 2010, Woods 2016 and Findlay et al. 2018) to exhibit functionally abnormal effect. Another variant at the same codon - c.5154G>T (p.Trp1718Cys) - demomstrates similar deleterious effect, and is reported in ClinVar as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269394	SCV001492182	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-12-17	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Trp1718 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15172985, 16528612, 20516115, 12491487, 23683081). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces tryptophan with serine at codon 1718 of the BRCA1 protein (p.Trp1718Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 28637432). ClinVar contains an entry for this variant (Variation ID: 55433). This variant has been reported to affect BRCA1 protein function (PMID: 20516115, 30209399). In addition, an algorithm developed specifically for the BRCA1 gene suggests that this missense change is likely to be deleterious (PMID: 28781887). Experimental studies have shown that this variant does not affect mRNA splicing (PMID: 25724305).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112538	SCV000145360	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112538	SCV001237783	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro