ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5153G>C (p.Trp1718Ser) (rs41293461)

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Total submissions: 5
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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 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 and 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.
Invitae RCV001269394 SCV001492182 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-17 criteria provided, single submitter clinical testing 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). 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. 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112538 SCV000145360 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112538 SCV001237783 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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