Submissions for variant NM_007294.4(BRCA1):c.5536C>T (p.Gln1846Ter)

dbSNP: rs80356873

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112699	SCV000300279	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.
Counsyl	RCV000112699	SCV000220262	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-24	criteria provided, single submitter	literature only
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112699	SCV000326354	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000112699	SCV002003988	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Invitae	RCV001853027	SCV002176324	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 10811118, 20104584, 21922593, 24504028). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects BRCA1 function (PMID: 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 55620). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 16287141, 29446198, 30702160). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1846*) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the BRCA1 protein.
Ambry Genetics	RCV002345359	SCV002653764	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The p.Q1846* pathogenic mutation (also known as c.5536C>T), located in coding exon 22 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5536. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 18 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in individuals with hereditary breast and/or ovarian cancer (Kroiss R et al. Hum. Mutat., 2005 Dec;26:583-9; Cavallone L et al. Fam. Cancer, 2010 Dec;9:507-17; Kuo WH et al. J. Hum. Genet., 2012 Feb;57:130-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001853027	SCV003933880	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5536C>T (p.Gln1846X) results in a premature termination codon, while it is not expected to exhibit nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant was absent in 250938 control chromosomes (gnomAD). c.5536C>T has been reported in the literature in multiple individuals from at least seven different families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g Kroiss_2005, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed that this variant was non-functional with respect to homology directed repair (HDR) activity (e.g. Findlay_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 16287141, 29446198). Four submitters, including an expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112699	SCV000145572	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112699	SCV001237656	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro