Submissions for variant NM_007294.4(BRCA1):c.3868A>T (p.Lys1290Ter)

dbSNP: rs80357254

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031135	SCV000300033	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	RCV000048361	SCV000076374	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-08	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: 37554). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 12491487, 25428789). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1290*) 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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031135	SCV000325775	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	RCV000048361	SCV000699078	pathogenic	Hereditary breast ovarian cancer syndrome	2019-08-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3868A>T (p.Lys1290X) 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 (c.3893C>A, p.Ser1298X; c.3937C>T, p.Gln1313X; c.4015G>T, p.Glu1339X). The variant was absent in 251164 control chromosomes (gnomAD). The variant, c.3868A>T, has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Judkins_2005, Olopade_2003, Churpek_2015, Mgbemena_2017, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions including one expert panel (ENIGMA) (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002354175	SCV002620016	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The p.K1290* pathogenic mutation (also known as c.3868A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3868. This changes the amino acid from a lysine to a stop codon within coding exon 9. This mutation has been identified in an African American woman diagnosed with early-onset breast cancer (Churpek JE et al, Breast Cancer Res. Treat. 2015 Jan; 149(1):31-9). 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.
Baylor Genetics	RCV000031135	SCV004215132	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-12	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031135	SCV000053734	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031135	SCV000144905	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	RCV000048361	SCV000587353	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001271016	SCV001451829	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing