ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5154G>T (p.Trp1718Cys) (rs80357239)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129752 SCV000184559 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-06 criteria provided, single submitter clinical testing ​The p.W1718C variant (also known as c.5154G>T or 5273G>T) is located in coding exon 17 of the BRCA1 gene. This alteration results from a G to T substitution at nucleotide position 5154. The tryptophan at codon 1718 is replaced by cysteine, an amino acid with dissimilar properties. This alteration is located in the BRCT domain of BRCA1 and results in destabilization due to defective protein folding (Williams RS et al. J. Biol. Chem. 2003 278:53007-53016). In one study, a transcriptional assay revealed that this alteration significantly decreased luciferase assay. In this study, the alteration was reported to segregate with breast and ovarian cancer in a family in which seven individuals across three generations were tested; however, a primary reference for this clinical information was not available (Mirkovic N et al. Cancer Res. 2004 Jun 1;64(11):3790-7). A more recent study also confirmed the strong adverse effect of this alteration on protein function, including decreased stability (4% of WT), protease activity (<10% of WT), binding specificity (<20% of WT), and transcription activity (<20% of WT) (Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90). This alteration has also been classified as non-functional based on a saturation genome editing functional assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000482189 SCV000572126 likely pathogenic not provided 2016-10-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5154G>T at the cDNA level, p.Trp1718Cys (W1718C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). Using alternate nomenclature, this variant would be defined as/ has been previously published as BRCA1 5273G>T. This variant has been observed in individuals with triple negative breast cancer and familial breast/ovarian cancer, and was reported to segregate with disease in a breast cancer kindred (Blay 2013, Eccles 2015, Couch 2015). Functional assays have found this variant to impact transcriptional activation and lead to protein destabilization (Williams 2003, Mirkovic 2004, Lee 2010). Additionally, this variant demonstrated cisplatin sensitivity and lack of growth rescue similar to pathogenic variants in mouse embryonic stem cells (Bouwman 2013).BRCA1 Trp1718Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Trp1718Cys occurs at a position that is conserved in mammals and is located in the first BRCT domain and a region known to interact with multiple other proteins (UniProt, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA1 Trp1718Cys to be a likely pathogenic variant.
Mendelics RCV000112539 SCV001140483 likely pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001328383 SCV001519505 pathogenic Hereditary breast and ovarian cancer syndrome 2021-02-27 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5154G>T (p.Trp1718Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250912 control chromosomes. c.5154G>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and to co-segregate with disease in at-least one multigenerational family with early onset breast cancer (example, Mirkovic_2004, LaDuca_2017, Blay_2013, Momozawa_2018). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of activity in multiple independent assays to include homology directed repair (HDR) capacity, protein folding stability, binding specificity to known functional target of the BRCA1 BRCT domain and transcriptional activity (example, Findlay_2018, Lee_2010). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001328383 SCV001576506 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 1718 of the BRCA1 protein (p.Trp1718Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with breast cancer in a family (PMID: 15172985), and has been observed in several individuals affected with hereditary breast and ovarian cancer (PMID: 12491487, 23683081, 26153499). ClinVar contains an entry for this variant (Variation ID: 55435). This variant has been reported to affect BRCA1 protein function (PMID: 15172985, 16528612, 20516115, 23867111, 14534301, 30209399). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112539 SCV000145362 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112539 SCV001237787 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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