Submissions for variant NM_007294.4(BRCA1):c.2866_2870del (p.Ser956fs)

dbSNP: rs80357819

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111951	SCV000282293	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195360	SCV000076006	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser956Valfs*13) 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 cancer and ovarian cancer (PMID: 7837387, 15146557). This variant is also known as 2982del5 and and 2985del5. ClinVar contains an entry for this variant (Variation ID: 54702). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000047993	SCV000209882	pathogenic	not provided	2023-12-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2985_2989del; This variant is associated with the following publications: (PMID: 26681312, 7837387, 20858050, 15146557, 26843898, 18042939, 30093976, 31825140, 28176296, 28724667, 34426522, 30702160, 30875412, 26236408, 33773534, 29446198, 34917121, 35864222)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000111951	SCV000296455	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-22	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000239021	SCV000296793	pathogenic	Familial cancer of breast	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111951	SCV000325483	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567133	SCV000660942	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-03	criteria provided, single submitter	clinical testing	The c.2866_2870delTCTCA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 5 nucleotides at nucleotide positions 2866 to 2870, causing a translational frameshift with a predicted alternate stop codon (p.S956Vfs*13). This mutation has been reported in multiple breast and/or ovarian cancer families (Shattuck-Eidens D et al. JAMA. 1995 Feb 15;273(7):535-41; Gorski B et al. Int J Cancer. 2004 Jul 10;110(5):683-6). This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119) as well as a cohort of 916 Chinese ovarian cancer patients (Shi T et al. Int. J. Cancer. 2017 05;140:2051-2059). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this mutation is also designated as 2982del5 and 2985del5 in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000567133	SCV000683066	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This variant deletes 5 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. This variant has been observed in individuals affected with breast cancer (PMID: 28724667) and ovarian cancer (PMID: 28176296) and in suspected hereditary breast and ovarian cancer families (PMID: 7837387, 15146557, 29446198). This variant has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000789). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195360	SCV001360673	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2866_2870delTCTCA (p.Ser956ValfsX13) 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. The variant was absent in 251368 control chromosomes (gnomAD). c.2866_2870delTCTCA has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Shattuck-Eidens_1995, Shi_2017, Bhaskaran_2019). 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. Eight ClinVar submitters including one expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000047993	SCV001716305	pathogenic	not provided	2020-07-17	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470739	SCV002767738	pathogenic	Fanconi anemia, complementation group S	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with risk of cancer (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. This gene is associated with autosomal recessive Fanconi Anemia, however, it is also associated with an increased risk for breast, ovarian, prostate, pancreatic or stomach cancer (OMIM, PMID: 26236408). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in an alternative transcript. This variant is non-coding in the BRCA1 NM_007298.3 and NM_007299.4 alternate transcripts (UCSC Genome Browser)]. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other loss of function variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple loss of function variants are present along the BRCA1 gene (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert review panel (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111951	SCV004021932	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser956Valfs*13) 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) nor in our local database. This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 7837387, 15146557 ,29446198). ClinVar contains an entry for this variant (Variation ID: 54702) reviewed by expert panel and classified as pathogenic . For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000111951	SCV004215065	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-12	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111951	SCV000144564	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-07	no assertion criteria provided	clinical testing