Submissions for variant NM_007294.4(BRCA1):c.929del (p.Gln310fs)

dbSNP: rs80357844

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031289	SCV000299507	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.
Ambry Genetics	RCV000131986	SCV000187044	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	The c.929delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 929, causing a translational frameshift with a predicted alternate stop codon (p.Q310Rfs*4). This mutation has been identified in several individuals and families with breast and/or ovarian cancer (Friedman LS et al. Am. J. Hum. Genet. 1995 Dec;57:1284-97; Couch FJ et al. N. Engl. J. Med. 1997 May;336:1409-15; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Gleicher N et al. PLoS One, 2014 Jul;9:e102370; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Schrader KA et al. Obstet Gynecol, 2012 Aug;120:235-40; Iau PT et al. Breast Cancer Res Treat, 2004 May;85:81-8). This alteration has also been designated as 1048delA in publications. 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.
GeneDx	RCV000235314	SCV000292505	pathogenic	not provided	2019-11-08	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 breast and/or ovarian cancer (Friedman 1995, Zhang 2011, Song 2014, Couch 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Also known as 1048delA; This variant is associated with the following publications: (PMID: 8533757, 24728189, 25452441, 21324516, 22798144, 29339979, 30720243)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031289	SCV000326465	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031289	SCV000564311	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131986	SCV001351493	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 identified in 1/251372 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.
Invitae	RCV000496711	SCV001590792	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln310Argfs*4) 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 (rs80357844, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and increasing risk of breast and ovarian cancers (PMID: 8533757, 9145677, 21324516, 29446198). This variant is also known as 1048delA. ClinVar contains an entry for this variant (Variation ID: 37708). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235314	SCV002046689	pathogenic	not provided	2021-03-10	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individuals and families affected with breast and/or ovarian cancer in the published literature (PMIDs: 8533757 (1995), 9145677 (1997), 21324516 (2011), and 24728189 (2014)). The frequency of this variant in the general population is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496711	SCV002103844	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.929delA (p.Gln310ArgfsX4) 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 251372 control chromosomes (gnomAD). c.929delA has been reported in the literature in multiple individuals affected with Hereditary Breast and/or Ovarian Cancer (examples: Song_2014 and Heramb_2018). These data indicate that the variant is very likely to be associated with disease. One expert panel (ENIGMA) and seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000235314	SCV003809180	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000031289	SCV004216910	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-09-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235314	SCV004563808	pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	The BRCA1 c.929del; p.Gln310ArgfsTer4 variant (rs80357844), also known as 1048delA using historical nomenclature, is reported in the literature in multiple individuals affected with breast/ovarian cancer (selected references: Heramb 2018, Friedman 1995, Zhang 2011). This variant 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 in exon 10, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, other truncating variants in this exon have been reported in individuals with breast/ovarian cancer and are considered pathogenic (selected reference: Sinilnikova 2006). It is also listed in the ClinVar database (Variation ID: 37708). Based on available information, this variant is considered to be pathogenic. References: Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Friedman LS et al. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet. 1995 Dec;57(6):1284-97. PMID: 8533757 Sinilnikova OM et al. BRCA1 and BRCA2 mutations in breast and ovarian cancer syndrome: reflection on the Creighton University historical series of high risk families. Fam Cancer. 2006;5(1):15-20. PMID: 16528604. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516.
Sharing Clinical Reports Project (SCRP)	RCV000031289	SCV000053894	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-09-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031289	SCV000143955	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	RCV000496711	SCV000587087	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research