Submissions for variant NM_007294.4(BRCA1):c.1116G>A (p.Trp372Ter)

dbSNP: rs80357468

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111553	SCV000299541	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.
Ambry Genetics	RCV000131844	SCV000186899	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The p.W372* pathogenic mutation (also known as c.1116G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1116. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This mutation has been previously identified in several hereditary breast/ovarian cancer cohorts (Shattuck-Eidens D, et al. JAMA. 1997 Oct; 278(15):1242-50; Li N, et al. Int. J. Gynecol. Cancer; 16 Suppl 1():172-8; Kim Y, et al. Oncotarget 2016 Feb;7(8):9600-12; Harter P et. al. PLoS ONE 2017 Oct;12(10):e0186043; Rebbeck TR et al. Hum. Mutat. 2018. 05;39(5):593-620). 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.
GeneDx	RCV000235123	SCV000210098	pathogenic	not provided	2023-11-25	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1235G>A; This variant is associated with the following publications: (PMID: 22010008, 25525159, 9333265, 10644434, 25452441, 29446198, 30702160, 26681312, 31825140, 28724667, 28888541, 11597388)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000111553	SCV000296331	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-04-27	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111553	SCV000324958	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496759	SCV001583698	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-04	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54135). This variant is also known as c.1235G>A. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and melanoma (PMID: 9333265, 11504767, 16515586, 16683254, 26681312, 26848529, 27656653, 28724667). This sequence change creates a premature translational stop signal (p.Trp372*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496759	SCV003801052	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1116G>A (p.Trp372X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251174 control chromosomes. c.1116G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. Seven 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496759	SCV004848126	pathogenic	Hereditary breast ovarian cancer syndrome	2018-08-09	criteria provided, single submitter	clinical testing	The p.Trp372X variant in BRCA1 has been reported in at least 2 individuals with breast cancer (Shattuck-Eidens 1997, Couch 2015) and one individual with melanoma (Susswein 2015). In addition, this variant was classified as Pathogenic on Setptember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299541.2). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 372 which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer syndrome in an autosomal dominant manner based upon case reports, absence from controls and predicted impact on protein. ACMG/AMP Criteria applied: PM2, PP4, PVS1 (Richards 2015).
Baylor Genetics	RCV000111553	SCV005058304	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-14	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111553	SCV000144015	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1998-08-26	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496759	SCV000587107	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785203	SCV000923771	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000111553	SCV004244134	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing