Submissions for variant NM_007294.4(BRCA1):c.5136G>A (p.Trp1712Ter)

gnomAD frequency: 0.00001  dbSNP: rs80357418

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077600	SCV000300208	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000048806	SCV000076819	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1712*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357418, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12920083, 16683254, 27836010). This variant is also known as c.5255G>A. ClinVar contains an entry for this variant (Variation ID: 55410). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131830	SCV000186885	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	The p.W1712* pathogenic mutation (also known as c.5136G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5136. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This alteration has been detected in numerous breast and/or ovarian cancer families (Ozcelik H et al. J. Med. Genet. 2003 Aug;40(8):e91; van der Hout AH et al. Hum Mutat. 2006 Jul;27(7):654-66; Schenkel LC et al. J Mol Diagn. 2016 Sep;18(5):657-667; Briceno-Balcazar I et al. Colomb Med (Cali). 2017 Jun 30;48(2):58-63). Of note, this alteration is designated as 5255G>A in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077600	SCV000326165	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000475804	SCV000540942	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000481118	SCV000567723	pathogenic	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); Observed in individuals with a personal or family history of breast and/or ovarian cancer (Ozcelik 2003, van der Hout 2006, Afghahi 2017, Briceo-Balczar 2017, Carter 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5255G>A; This variant is associated with the following publications: (PMID: 28087643, 12920083, 16683254, 16944269, 16267036, 27376475, 25525159, 27067391, 29021639, 30322717, 30209399, 29446198, 30787465)
Color Diagnostics, LLC DBA Color Health	RCV000131830	SCV000908990	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 17 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 12920083, 16683254, 27836010, 29021639). This variant has been identified in 2/251292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048806	SCV000918769	pathogenic	Hereditary breast ovarian cancer syndrome	2018-08-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5136G>A (p.Trp1712X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246144 control chromosomes (gnomAD). The variant, c.5136G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Briceno-Balcazar_2017, Ozcelik_2003, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
New York Genome Center	RCV000077600	SCV003925198	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-06-16	criteria provided, single submitter	clinical testing	The c.5136G>A variant in BRCA1 has previously been reported in individuals with hereditary breast and/or ovarian cancer [PMID:12920083, 30322717, 29446198,30787465] and it has been curated as pathogenic by an expert panel in ClinVar [ClinVar ID: 55410]. The c.5136G>A variant is observed in 3 alleles with 0 homozygote in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.5136G>A variant in BRCA1 is located in exon 17 of this 23-exon gene, is predicted to incorporate a premature termination codon (p.(Trp1712Ter), and is demonstrated to result in loss-of-function by saturation genome editing assays [PMID: 30209399]. Multiple loss-of-function variants downstream to the c.5136G>A variant have been reported in the literature and ClinVar in individuals with hereditary breast and/or ovarian cancer. Based on available evidence this c.5136G>A p.(Trp1712Ter) variant identified in BRCA1 is classified as Pathogenic.
Baylor Genetics	RCV000077600	SCV004216975	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-04-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077600	SCV000109403	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-07-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077600	SCV000145322	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048806	SCV000587468	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000077600	SCV001242190	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000077600	SCV004243946	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing