Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_007294.4(BRCA1):c.5154G>T(p.Trp1718Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 17-43063372-C-A is Pathogenic according to our data. Variant chr17-43063372-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3Uncertain:1Other:1
Pathogenic, no assertion criteria provided
case-control
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)
May 24, 2021
- -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
-
- -
Likely pathogenic, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
Likely pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Jul 18, 2022
- -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jul 12, 2023
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). -
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Feb 27, 2021
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. -
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided
research
Laboratory for Genotyping Development, RIKEN
Jul 01, 2021
- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Nov 11, 2023
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) -
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 28, 2023
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. -