Submissions for variant NM_007294.4(BRCA1):c.3268C>T (p.Gln1090Ter)

dbSNP: rs80357402

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112042	SCV000299904	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	RCV000112042	SCV000325595	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	RCV000779899	SCV000916799	pathogenic	Hereditary breast ovarian cancer syndrome	2018-08-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3268C>T (p.Gln1090X) 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 (e.g. c.3288_3289delAA (p.Leu1098fsX4), c.3296delC (p.Pro1099fsX10), c.3331C>T (p.Gln1111X)). The variant was absent in 276164 control chromosomes (gnomAD). c.3268C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Gao 2000, Fackenthal 2012, Wong-Brown 2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001019530	SCV001180900	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	The p.Q1090* pathogenic mutation (also known as c.3268C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3268. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration was identified in an African breast cancer family and in a Polish patient with triple negative breast cancer (Gao Q et al. Hum. Genet., 2000 Aug;107:192-4; Wong-Brown MW et al. Breast Cancer Res. Treat., 2015 Feb;150:71-80). 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.
Color Diagnostics, LLC DBA Color Health	RCV001019530	SCV001344322	pathogenic	Hereditary cancer-predisposing syndrome	2019-11-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 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 suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 11030418, 22739995, 25682074). 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. Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV000779899	SCV001579544	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1090*) 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 and/or ovarian cancer (PMID: 11030418, 25682074, 29446198). ClinVar contains an entry for this variant (Variation ID: 54815). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112042	SCV000144695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785407	SCV000923979	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research