Submissions for variant NM_007294.4(BRCA1):c.2017G>T (p.Glu673Ter)

dbSNP: rs80357391

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111751	SCV000299686	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	RCV000131903	SCV000186958	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-30	criteria provided, single submitter	clinical testing	The p.E673* pathogenic mutation (also known as c.2017G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2017. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Olopade OI et al. Cancer, 2003 Jan;97:236-45; Beristain E et al, 2010 Jun;1:91-9; Briceño-Balcázar I et al. Colomb. Med., 2017 Jun;48:58-63; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Adedokun B et al. Cancer Epidemiol. Biomarkers Prev., 2020 02;29:359-367). 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	RCV000212166	SCV000210118	pathogenic	not provided	2014-07-11	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA1 c.2017G>T at the cDNA level and p.Glu673Ter (E673X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in one woman with breast cancer and in another with a personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome (Olopade 2003, Beristain 2010) and is considered pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111751	SCV000325213	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212166	SCV001249210	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV001387510	SCV001588166	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu673*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 22460208). ClinVar contains an entry for this variant (Variation ID: 54436). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000111751	SCV004211724	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-11-08	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111751	SCV000144276	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-12-30	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000111751	SCV002589091	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing