Submissions for variant NM_007294.4(BRCA1):c.2125_2126insA (p.Phe709fs)

dbSNP: rs80357871

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083179	SCV000299702	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047722	SCV000075735	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe709Tyrfs*3) 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: 10200350, 16905680, 24549055, 25884701, 27083178). This variant is also known as 2244insA. ClinVar contains an entry for this variant (Variation ID: 54469). For these reasons, this variant has been classified as Pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083179	SCV000195901	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083179	SCV000325244	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000483700	SCV000566679	pathogenic	not provided	2024-05-29	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 2244_2245insA and 2244insA; This variant is associated with the following publications: (PMID: 30145549, 16905680, 25884701, 10200350, 20694749, 24549055, 27446417, 28478614, 32894085, 32300229, 35578052, 27083178, 29446198, 22762150)
Mendelics	RCV000083179	SCV001140583	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014537	SCV001175255	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The c.2125_2126insA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from an insertion of one nucleotide at position 2125, causing a translational frameshift with a predicted alternate stop codon (p.F709Yfs*3). This alteration has been reported in numerous individuals with personal and/or family history consistent with hereditary breast and ovarian cancer syndrome (Laplace-Marieze V et al. Int. J. Oncol., 1999 May;14:971-7; Simard J et al. J. Med. Genet., 2007 Feb;44:107-21; Lecarpentier J et al. Breast Cancer Res., 2012 Jul;14:R99; Castéra L et al. Eur. J. Hum. Genet., 2014 Nov;22:1305-13; Belanger MH et al. J Ovarian Res, 2015 Mar;8:1; González-Rivera M et al. Breast Cancer Res. Treat., 2016 04;156:507-515; Jouali F et al. Oncol Lett, 2016 Aug;12:1192-1196; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 2244insA, c.2126insA, and c.2126_2127insA in published literature. 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	RCV001014537	SCV001352954	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-10	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has been reported with individuals affected with breast and/or ovarian cancer (PMID: 16905680, 24549055, 25884701, 27083178, 20694749, 28478614). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047722	SCV001363875	pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2125_2126insA (p.Phe709TyrfsX3) 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 251170 control chromosomes. c.2125_2126insA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Laplcae-Marieze_1999, Simard_2007, Rebbeck_2018). 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. Seven 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483700	SCV001469987	pathogenic	not provided	2020-04-03	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000083179	SCV002104294	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083179	SCV000115253	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083179	SCV000144308	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047722	SCV000587185	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735501	SCV000863639	pathogenic	Breast and/or ovarian cancer	2012-03-27	no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000083179	SCV003927166	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A known pathogenic mutation was detected in the BRCA1 gene (c.2125_2126insA). This sequence change creates a premature translational stop signal (p.Phe709Tyrfs*3) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases ( gnomAD). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 10200350, 16905680, 24549055, 25884701, 27083178). This variant is also known as 2244insA in the literature. ClinVar contains an entry for this variant (Variation ID: 54469). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. This variant was confirmed by Sanger Sequencing . Pathogenic mutations in the BRCA1 gene cause Hereditary Breast/Ovarian Cancer syndrome (HBOC). Carriers of a deleterious BRCA1 gene mutation are at: 50%-80% risk of developing breast cancer [general population at 12%]. 21.1% within 10 yrs and 83% by age 70 risk of developing second primary breast [general population at 2% within 5 years]. 24-%-40% risk of developing ovarian cancer [general population at 1-2%]. 1%-2% risk of developing male breast cancer [general population at 0.1%]. Up to 30% risk developing prostate cancer [general population at 15-18%]. 1%-3% risk developing pancreatic cancer [general population at 0.5%]. The Breast Cancer Linkage Consortium reported statistically significantly increased relative risks for cancers of the uterine body and cervix (only in heterozygous women age <65 years), with relative risks of 2.6, and 3.7 respectively [Thompson & Easton 2002]. Germline pathogenic variants in BRCA1 are inherited in an autosomal dominant manner. The majority of individuals with a BRCA1 pathogenic variant have inherited it from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from prophylactic surgery, or early death, not all individuals with a BRCA1 pathogenic variant have a parent affected with cancer.