Submissions for variant NM_007294.4(BRCA1):c.280C>T (p.Gln94Ter)

dbSNP: rs886037972

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241148	SCV000299435	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241148	SCV000325469	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779883	SCV000916770	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.280C>T (p.Gln94X) 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 (eg. c.303T>G, p.Tyr101X; c.427G>T, p.Glu143X; c.470_471delCT, p.Ser157X). The variant was absent in 121322 control chromosomes (ExAC). The variant, c.280C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Kwong_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001016654	SCV001177630	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-31	criteria provided, single submitter	clinical testing	The p.Q94* pathogenic mutation (also known as c.280C>T), located in coding exon 4 of the BRCA1 gene, results from a C to T substitution at nucleotide position 280. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration has been reported in individuals diagnosed with breast and/or ovarian cancer (Kwong A et al. J Mol Diagn. 2016 07;18:580-94; Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779883	SCV001591102	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln94*) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 254372). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 27157322, 29446198, 30078507, 30702160). This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV001016654	SCV004361125	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools indicate that this variant may impact splicing. A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay and it also reduces the abundance of BRCA1 mRNA (PMID: 30209399). This variant has been reported in an individual affected with breast cancer (PMID: 26187060). This variant has not been identified 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.
Brotman Baty Institute, University of Washington	RCV000241148	SCV001238577	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro