Submissions for variant NM_007294.4(BRCA1):c.4339C>T (p.Gln1447Ter)

dbSNP: rs80357067

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077570	SCV000300105	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	RCV000077570	SCV000325924	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000448320	SCV000537673	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary breast and/or ovarian cancer (PMID: 17319787, 21203900, 31409081). 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.
Invitae	RCV001381002	SCV001579251	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55173). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 17319787, 18489799). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1447*) 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	RCV003398636	SCV004121755	pathogenic	Familial prostate carcinoma	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4339C>T (p.Gln1447X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251344 control chromosomes. c.4339C>T has been reported in the literature in at-least one individual affected with Cancer (example, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29446198). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000077570	SCV004211762	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-04-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477451	SCV004219399	pathogenic	not provided	2023-02-06	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a family with hereditary breast and/or ovarian cancer (HBOC) (PMID: 17319787 (2007), 21203900 (2011)) and individuals and families with a high risk of HBOC (PMID: 29446198 (2018), 31409081 (2019)). Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077570	SCV000109373	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-06-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077570	SCV000145061	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001271023	SCV001451837	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000077570	SCV003927185	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A known pathogenic mutation was detected in the BRCA1 gene (c.4339C>T). This sequence change creates a premature translational stop signal (p.Gln1447*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD genomes. This variant has been observed in several individuals with hereditary breast and/or ovarian cancer (PMID: 17319787, 18489799, 21203900, 31409081). ClinVar contains an entry for this variant (Variation ID: 55173) with 7 submissions, all of which classify it as pathegenic, 3 stars and reviewd by an expert panel. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic.