Submissions for variant NM_007294.4(BRCA1):c.3485del (p.Asp1162fs)

gnomAD frequency: 0.00001  dbSNP: rs80357509

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031112	SCV000299952	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	RCV000048213	SCV000076226	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1162Valfs*48) 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 present in population databases (rs80357509, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150151, 16683254, 24010542, 25452441, 26681312). This variant is also known as 3604delA, c.3625delA, and 3741delA. ClinVar contains an entry for this variant (Variation ID: 37531). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000159918	SCV000210041	pathogenic	not provided	2023-03-07	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; Observed in hereditary breast and ovarian cancer families, and is a common variant in Finnish and Dutch populations (Peelen et al., 1997; Vehmanen et al., 1997; Syrjakoski et al., 2000; Janavicius et al., 2010; Brohet et al., 2014); 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 3604delA; This variant is associated with the following publications: (PMID: 23199084, 16683254, 30927251, 29922827, 28888541, 9667259, 24285858, 26681312, 9361038, 10995809, 25452441, 28324225, 11773283, 30720243, 30322717, 9150151, 11597388, 33558524, 24010542, 34697415)
Ambry Genetics	RCV000220121	SCV000273760	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The c.3485delA (p.D1162Vfs*48) alteration, located in exon 10 (coding exon 9) of the BRCA1 gene, consists of a deletion of one nucleotide at position 3485, causing a translational frameshift with a predicted alternate stop codon after 48 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251278) total alleles studied. The highest observed frequency was 0.001% (1/113680) of European (non-Finnish) alleles. This variant has been reported in multiple hereditary breast and ovarian cancer (HBOC) families (Peelen, 1997; Vehmanen, 1997; Frank, 1998; Ligtenberg, 1999; Sarantaus, 2001; Verhoog, 2001; Meindl, 2002; Meisel, 2017; Carter, 2018; Nurmi, 2019; Moradian, 2021; Breast Cancer Association, 2021). Of note, this alteration is also designated as 3604delA in published literature. Based on the available evidence, this alteration is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031112	SCV000325669	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159918	SCV000600335	pathogenic	not provided	2022-01-24	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 28324225 (2017), 26681312 (2015), 25452441 (2015), 23192404 (2013), 9150151 (1997)). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048213	SCV000605763	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-27	criteria provided, single submitter	clinical testing	The p.Asp1162fs variant in BRCA1 has been reported in >30 individuals with BRCA1 -associated cancers (Peelen 1997, Breast Cancer Information Core (BIC) database) and was absent from large population studies. This variant is predicted to caus e a frameshift, which alters the protein?s amino acid sequence beginning at posi tion 1162 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Hete rozygous loss of function of function of the BRCA1 gene is an established diseas e mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this va riant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299952.2). In summary, the p.Asp1162fs varian t meets criteria to be classified as pathogenic for HBOC in an autosomal dominan t manner.
Color Diagnostics, LLC DBA Color Health	RCV000220121	SCV000688438	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	This variant deletes 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. This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 9150151, 9361038, 9667259, 10995809, 16683254, 24285858, 25452441, 26681312, 28324225, 30322717, 30927251). This variant has been identified in 81 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). A large breast cancer case-control study (PMID: 33471991) has reported this variant in 5/60461 cases and 0/53461 controls. This variant has been identified in 1/251278 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048213	SCV000699038	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3485delA (p.Asp1162ValfsX48) 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 allele was found at a frequency of 4e-06 in 251278 control chromosomes. c.3485delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Vehmanen_1997, Peelen_1997, Judkins_2005, Rummel_2013). These data indicate that the variant is very likely to be associated with disease. Twelve 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031112	SCV000744634	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159918	SCV001447283	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159918	SCV002047830	pathogenic	not provided	2021-08-28	criteria provided, single submitter	clinical testing	The BRCA1 c.3485delA; p.Asp1162ValfsTer48 variant (rs803575090), also published as 3604delA, is reported in the literature in several individuals and families with hereditary breast and ovarian cancer (Carter 2018, Couch 2015, Meisel 2017, Susswein 2016). The variant is reported in the ClinVar database (Variation ID: 37531) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. PMID: 25452441. Meisel C et al. Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. Arch Gynecol Obstet. 2017 May;295(5):1227-1238. PMID: 28324225. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. PMID: 26681312.
Revvity Omics, Revvity	RCV000159918	SCV003810355	pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159918	SCV004009794	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PS4:Moderate, PP1
Unidad Asesoramiento Genetico Oncologico Falp, Instituto Oncologico Fundacion Arturo Lopez Perez	RCV000031112	SCV004024157	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031112	SCV004211751	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-06-04	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031112	SCV005045941	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031112	SCV005900215	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
Sharing Clinical Reports Project (SCRP)	RCV000031112	SCV000053709	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031112	SCV000144775	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Curoverse	RCV000048213	SCV000245336	pathogenic	Hereditary breast ovarian cancer syndrome	2015-08-01	no assertion criteria provided	research	Frameshifts in BRCA1 are considered pathogenic, and this is a BRCA1 Asp1162Val frameshift variant in exon 10
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000408844	SCV000484951	pathogenic	Familial cancer of breast		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000048213	SCV000587316	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031112	SCV000733627	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000031112	SCV000987232	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA1 p.Asp1162Valfs variant is a known pathogenic variant also in exon 11 in a non-functional domain just before the BRSTCANCERI domain (S1180-1200Q aa) (PMID: 10198641) and in a mutational hotspot with 34 pathogenic variants (PM1 Pathogenic Moderate). The deletion causes a frameshift, which changes an Aspartic Acid to a Valine at codon 1162, and creates a premature stop codon at position 48 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.00000398 which is less the threshold 0.0001 for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000299952.2) (PP5 Pathogenic Supporting). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). In this study the variant Asp1162Valfs was found in a 51- year-old female with unilateral breast cancer and strong family history. Therefore, this variant was classified as a Pathogenic.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000159918	SCV001905790	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000048213	SCV004228727	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-16-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
BRCAlab, Lund University	RCV000031112	SCV004244043	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing