Submissions for variant NM_007294.4(BRCA1):c.135-1G>T

gnomAD frequency: 0.00001  dbSNP: rs80358158

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566758	SCV004101414	pathogenic	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.135-1G>T variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 3 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RNAseq demonstrated that the variant impacts splicing by resulting in skipping of exon 4 from the transcript (PMID: 30101128). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 234999878.51 (based on Cosegregation LR=9528; Pathology LR=2.009; Family History LR=12277.7), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PS3, PP4_Very strong).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047435	SCV000075448	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs80358158, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with a personal or family history breast cancer (PMID: 9333265, 11179017, 16211554, 18445692, 20020529, 26187060). This variant is also known as IVS4-1G>T and IVS3-1G>T. ClinVar contains an entry for this variant (Variation ID: 37404). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 20020529). Studies have shown that disruption of this splice site results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 16211554, 24212087; Invitae). This variant disrupts the p.Cys64 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7894491, 11320250, 15131401, 23867111, 24516540, 26246475, 27257965, 29446198). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131843	SCV000186898	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	The c.135-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 3 of the BRCA1 gene. This mutation has been identified in multiple breast, ovarian and/or prostate cancer families (Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Rashid MU et al. Int. J. Cancer 2006 Dec;119(12):2832-9; Tesoriero AA et al. Hum. Mutat. 2005 Nov;26(5):495. Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68(3):700-10. Shattuck-Eidens D et al. JAMA 1997 Oct;278(15):1242-50; Willems AJ et al. Clin. Cancer Res. 2008; 14:2953-61). This variant gives rise to an in -frame deletion of coding exon 3 (also known as exon 5 in the literature-Tesoriero AA et al. Hum Mutat. 2005 Nov;26(5):495; Farber-Katz S et al. Front Oncol, 2018 Jul;8:286). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Of note, this alteration is also designated as IVS3-1G>T and IVS4-1G>T in the published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
GeneDx	RCV000236913	SCV000292501	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in an in-frame loss of the adjacent exon, which is located in the critical RING finger domain, in a gene for which loss of function is a known mechanism of disease (PMID: 16211554, 8944023, 20104584, 23239986, 24389207); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 254-1G>T, IVS4-1G>T; This variant is associated with the following publications: (PMID: 9333265, 21285146, 21324516, 27553291, 16683254, 28888541, 20020529, 11179017, 25525159, 18445692, 24212087, 16998791, 26187060, 21965345, 21769658, 16528604, 23239986, 30209399, 29446198, 29625052, 26689913, 30787465, 35464868, 29922827, 20104584, 24389207, 8944023, 30720243, 31131967, 32885271, 18824701, 30101128, 36451132, 34887416, 25452441, 16211554)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236913	SCV000296367	pathogenic	not provided	2020-11-17	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and interferes with normal BRCA1 mRNA splicing. In the published literature, this variant has been reported in multiple individuals with breast and/or ovarian cancer and shown to cause an in-frame deletion of exon 5 of the BRCA1 gene from experimental studies (PMID: 31131967 (2019), 30209399 (2018), 26187060 (2015), 25452441 (2015), 24212087 (2014), 21324516 (2011), 20020529 (2010), 18824701 (2008), 16211554 (2005), 9333265 (1997)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030985	SCV000325042	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000030985	SCV000677633	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047435	SCV000698850	pathogenic	Hereditary breast ovarian cancer syndrome	2016-05-20	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.135-1G>T variant involves the alteration of a conserved intronic nucleotide located at a canonical splice site. Mutation taster predicts a damaging outcome for this variant along with 5/5 in silico splice site prediction algorithms predicting the loss of the splice acceptor site. These predictions were confirmed by Tesoriero_HM_2005 which demonstrated the variant to result in exon skipping that creates an in-frame deletion of 26 amino acids from exon 5. The variant was found in 1/111484 control chromosomes at a frequency of 0.000009, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in several HBOC patients and in at least one HBOC family it co-segregated with the disease (Tesoriero_HM_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as a Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131843	SCV000903751	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 3 of the BRCA1 gene. RNA studies have shown that this variant impacts the splicing of exon 4 that partially encodes the RING domain, which is important for BRCA1 function and is noted to have clinically relevant mutations (PMID: 16211554, 22737296, 30101128). A functional study has shown that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in at least 7 individuals affected with breast and ovarian cancer (PMID: 11179017, 16211554, 21324516, 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA1_000503) and an individual affected with prostate cancer with a family history of breast cancer (PMID: 18445692). This variant also has been reported with a co-segregation likelihood ratio for pathogenicity of 9528 in one pedigree (PMID: 31131967). This variant has been identified in 2/280296 chromosomes 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.
Revvity Omics, Revvity	RCV000236913	SCV002017840	pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047435	SCV002026039	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504838	SCV002810119	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-05-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000030985	SCV004216940	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-03-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047435	SCV004848063	pathogenic	Hereditary breast ovarian cancer syndrome	2019-01-17	criteria provided, single submitter	clinical testing	The c.135-1G>T variant in BRCA1 has been reported in more than 30 individuals with BRCA1-associated cancers and segregated with breast cancer in 10 relatives from 1 family (Shattuck-Eidens 1997, Risch 2001, Tesoriero 2005, Willems 2008, Rashid 2016, Breast Cancer Information Core (BIC)). This variant has been identified in 2/128060 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80358158). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and functional studies have shown it results in an in-frame deletion of 26 amino acids(Tesoriero 2005, Wappenschmidt 2012). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PM4.
Sharing Clinical Reports Project (SCRP)	RCV000030985	SCV000053577	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030985	SCV000144430	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047435	SCV000587018	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000030985	SCV001241566	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358046	SCV001553688	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.135-1G>T variant has been shown to give rise to an in-frame deletion of exon 5 (BRCA1 c.135_212del) that is predicted to encode 26 amino acids. One study used the multifactorial likelihood analysis and variant segregation in families by Bayes analysis to evaluate the clinical significance of this variant. The Bayes scores from a single family with BRCA1 c.135-1G>T was 9528:1, providing strong evidence of causality for this variant; in addition, inclusion of pathology features gave an overall likelihood of causality of 28108:1 (Spurdle_2010). The variant was identified in dbSNP (ID: rs80358158) as “With Pathogenic allele” and in the Clinvitae and Clinvar databases as pathogenic by Ambry Genetics; GeneDx; Quest Diagnostics Nichols Institute San Juan Capistrano; Consortium of Investigators of Modifiers of BRCA1/2, University of Cambridge and SCRP. The variant was further identified in ARUP Laboratories BRCA Mutations Database as definitely pathogenic and in the Fanconi Anemia Mutation Database (LOVD), which refer to the multifactorial likelihood score of 28108:1. The variant was not identified in the COSMIC, GeneInsight COGR, UMD, and the BIC databases. In addition, the variant was identified in the the Exome Aggregation Consortium database (August 8th 2016) in 1 of 111484 chromosomes (freq. 0.000009) in the European (Non-Finnish) population but not seen in the African, East Asian, European (Finnish), Latino and South Asian populations. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the genome Aggregation Database (beta, October 19th 2016. The c.135-1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.