Submissions for variant NM_007294.4(BRCA1):c.2901_2902dup (p.Pro968fs)

dbSNP: rs398122670

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)	RCV000077119	SCV000323535	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000204430	SCV000260016	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro968Leufs*33) 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 ovarian cancer (PMID: 23683081, 24137399, 25136594). This variant is also known as c.2901insCT and c.2900_2901dupCT. ClinVar contains an entry for this variant (Variation ID: 91602). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077119	SCV000296471	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-13	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077119	SCV000325494	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568770	SCV000661015	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-21	criteria provided, single submitter	clinical testing	The c.2901_2902dupTC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of TC at nucleotide position 2901, causing a translational frameshift with a predicted alternate stop codon (p.P968Lfs*33). This mutation has been detected in multiple individuals with personal and/or family histories of breast and ovarian cancer, and has been seen specifically in families of Northern Spanish (Asturian) descent, suggesting a possible founder effect (Blay P et al. BMC Cancer, 2013 May;13:243; Salgado J et al. Oncol Lett, 2013 Sep;6:725-727; Cardoso FC et al. Hum. Genomics, 2018 08;12:39; Ruiz de Sabando A et al. BMC Cancer, 2019 Nov;19:1145). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000204430	SCV000916791	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2901_2902dupTC (p.Pro968LeufsX33) 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. The variant was absent in 246162 control chromosomes (gnomAD). The variant, c.2901_2902dupTC (also known as 3020insCT, 2901incCT, 2900_2901dupCT) has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, including in one family where it segregated with disease (Blay_2013, Ruiz_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000568770	SCV001346140	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-25	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and 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 observed in multiple individuals and families affected with breast and ovarian cancer (PMID: 23683081, 24137399, 25136594, 30103829, 31771539). 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.
Sema4, Sema4	RCV000568770	SCV002538162	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	curation
Baylor Genetics	RCV000077119	SCV004216922	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077119	SCV000108916	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-15	no assertion criteria provided	clinical testing