Submissions for variant NM_007294.4(BRCA1):c.933del (p.Gly312fs)

dbSNP: rs1135401839

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661200	SCV000783457	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496544	SCV000916729	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-03-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.933delT (p.Gly312AlafsX2) 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.981_982delAT, p.Cys328X; c.1016dupA, p.Val340fsX6; c.1054G>T, p.Glu352X). The variant was absent in 246256 control chromosomes (gnomAD and literature). c.933delT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Juwle_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496544	SCV001377099	pathogenic	Hereditary breast ovarian cancer syndrome	2021-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly312Alafs*2) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with breast cancer (PMID: 22752604). ClinVar contains an entry for this variant (Variation ID: 431204). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000661200	SCV004047717	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The frameshift variant c.933del (p.Gly312AlafsTer2) in the BRCA1 gene has been reported previously in heterozygous state in a family affected affected with breast cancer (Juwle A. et al., 2012). The variant is novel (not in any individuals) in gnomAD Exomes and in 1000 Genomes. It is submitted in ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005018833	SCV005647183	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2024-06-04	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496544	SCV000587089	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research