Submissions for variant NM_007294.4(BRCA1):c.2199del (p.Lys734fs)

dbSNP: rs80357944

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077095	SCV000299715	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.
GeneDx	RCV000235485	SCV000292511	pathogenic	not provided	2023-11-15	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 2318del; This variant is associated with the following publications: (PMID: 16267036, 25072261, 18762988, 26681682, 29446198)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077095	SCV000325285	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077095	SCV000786107	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235485	SCV000887639	pathogenic	not provided	2018-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771401	SCV000903749	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-05	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with breast cancer and pancreatic cancer (PMID: 18762988, 26681682) and in 4 families among the CIMBA participants (PMID: 29446198; https://cimba.ccge.medschl.cam.ac.uk/). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496526	SCV000958701	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 91578). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with pancreatic cancer and breast cancer (PMID: 18762988, 26681682, 29446198). This sequence change creates a premature translational stop signal (p.Lys734Asnfs*2) 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).
Ambry Genetics	RCV000771401	SCV002728608	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	clinical testing	The c.2199delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2199, causing a translational frameshift with a predicted alternate stop codon (p.K734Nfs*2). This alteration, designated as 2318delG, has been identified in breast and pancreatic cancer patients (Al-Sukhni W et al. Hum Genet. 2008 Oct;124:271-8; Eccles DM et al. Ann Oncol. 2016 Mar;27:467-73). This alteration has also identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). 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.
Revvity Omics, Revvity	RCV000235485	SCV003819089	likely pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077095	SCV000108892	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077095	SCV000144332	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	RCV000496526	SCV000587198	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research