Submissions for variant NM_007294.4(BRCA1):c.220C>T (p.Gln74Ter)

dbSNP: rs80357234

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112044	SCV000299427	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	RCV000047758	SCV000075771	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln74*) 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 breast or ovarian cancer (PMID: 9150149). ClinVar contains an entry for this variant (Variation ID: 54499). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112044	SCV000325289	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000414657	SCV000490907	pathogenic	not provided	2017-06-09	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.220C>T at the cDNA level and p.Gln74Ter (Q74X) at the protein level. Using alternate nomenclature, this variant has been published as BRCA1 339C>T. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>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 individuals with hereditary breast and ovarian cancer (Stoppa-Lyonnet 1997, Kiechle 2000, Kwong 2016) and is considered pathogenic.
Ambry Genetics	RCV000572393	SCV000665795	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-28	criteria provided, single submitter	clinical testing	The p.Q74* pathogenic mutation (also known as c.220C>T), located in coding exon 4 of the BRCA1 gene, results from a C to T substitution at nucleotide position 220. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been previously reported in high-risk breast and/or ovarian cancer cohorts (Stoppa-Lyonnet D et al. Am. J. Hum. Genet., 1997 May;60:1021-30; Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Singh et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196 ). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047758	SCV000698929	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-24	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.220C>T (p.Gln74X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. p.Tyr101X, p.Glu143X, p.Ser157X, etc.). This variant is absent in 121250 control chromosomes from ExAC. This variant has been reported in several HBOC affected patients in literature (Stoppa-Lyonnet_1997, Kiechle_2000, Lecarpentier_2012, Bjorkman_2015, Wang_2015, Kwong_2016, Tung_2016, Lang_2017) and clinical databases (UMD, ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
3DMed Clinical Laboratory Inc	RCV000677814	SCV000803974	pathogenic	Ovarian cancer	2017-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000414657	SCV001450019	pathogenic	not provided	2018-08-13	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000112044	SCV002003990	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000112044	SCV004216854	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-01-11	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112044	SCV000144697	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047758	SCV000587040	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112044	SCV001238492	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000414657	SCV001906292	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414657	SCV001957529	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112044	SCV004244182	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing