ClinVar Miner

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

dbSNP: rs80357239
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Total submissions: 9
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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 2023-03-28 criteria provided, single submitter clinical testing The p.W1718C variant (also known as c.5154G>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. A study 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 2023-11-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5273G>T; This variant is associated with the following publications: (PMID: 26153499, 14534301, 25724305, 25452441, 12491487, 20516115, 15172985, 23683081, 16528612, 23867111, 12270722, 30209399, 33087888, 28152038, 25348405, 35665744, 32546644, 30765603)
Mendelics RCV000112539 SCV001140483 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 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 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 ovarian cancer syndrome 2023-07-12 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 15172985, 16528612, 20516115, 23867111, 30209399). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 55435). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 12491487, 15172985, 23683081, 25452441, 26153499, 30287823, 31112363). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1718 of the BRCA1 protein (p.Trp1718Cys).
Baylor Genetics RCV000112539 SCV004216941 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-07-18 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112539 SCV000145362 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000112539 SCV001237787 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
Laboratory for Genotyping Development, RIKEN RCV003162418 SCV002758197 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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