Submissions for variant NM_007294.4(BRCA1):c.329dup (p.Glu111fs)

dbSNP: rs80357604

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031101	SCV000299442	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	RCV000195362	SCV000076145	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu111Glyfs*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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10644434, 15146556, 20858050, 22762150, 25452441, 26577449). This variant is also known as 448insA. ClinVar contains an entry for this variant (Variation ID: 54827). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000048132	SCV000210000	pathogenic	not provided	2021-01-19	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 individuals with a personal and family history of breast and/or ovarian cancer (Wagner 1999, Meindl 2002, Reeves 2004, George 2016, Rummel 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 448dupA; This variant is associated with the following publications: (PMID: 28503720, 29625052, 26577449, 11802209, 10644434, 16267036, 20858050, 22762150, 25452441, 21702907, 27406733, 15146556, 29297111, 29310832, 26689913)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031101	SCV000267681	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000239071	SCV000296785	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	RCV000031101	SCV000325604	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031101	SCV000489151	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575183	SCV000665804	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-18	criteria provided, single submitter	clinical testing	The c.329dupA pathogenic mutation, located in coding exon 5 of the BRCA1 gene, results from a duplication of A at nucleotide position 329, causing a translational frameshift with a predicted alternate stop codon (p.E111Gfs*3). This mutation has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Reeves M et al. Int J Cancer. 2004 Jul 10;110(5):677-82; Lecarpentier J et al. Breast Cancer Res., 2012 Jul;14:R99; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Apessos A et al. Cancer Genet, 2018 Jan;220:1-12; Alhuqail AJ et al. Breast Cancer Res. Treat., 2018 Apr;168:695-702; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). Of note, this alteration is also designated as 448insA and 448dupA 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048132	SCV000887664	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000048132	SCV001446745	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000031101	SCV002579243	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000048132	SCV004026821	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031101	SCV004215020	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195362	SCV004222969	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.329dupA (p.Glu111GlyfsX3) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.329dupA has been reported in the literature in individuals affected with breast cancer (e.g. Zheng_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30130155). 12 submitters, including an expert panel (ENIGMA), have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031101	SCV004698084	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-13	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195362	SCV004848391	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The p.Glu111GlyfsX3 variant in BRCA1 has been reported in at least 18 individuals with BRCA1-related cancer (first reported by Wagner 1999 PMID: 10644434). It was absent from large population studies. This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 54827). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 111 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Four other variants: c.331del (p.Glu111fs); c.330_331insA (p.Glu111fs); c.329delA (p.Lys110fs); and c.329_330del (p.Lys110fs) have been identified in individuals with HBOC and are classified as pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM5_Strong, PM2, PS4_Strong.
Sharing Clinical Reports Project (SCRP)	RCV000031101	SCV000053697	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031101	SCV000145076	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000195362	SCV000587047	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031101	SCV004244175	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing