Submissions for variant NM_007294.4(BRCA1):c.5035del (p.Asn1678_Leu1679insTer)

dbSNP: rs80357896

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112469	SCV000300188	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	RCV000497274	SCV000210054	pathogenic	not provided	2014-07-11	criteria provided, single submitter	clinical testing	This deletion of one nucleotide is denoted BRCA1 c.5035delC at the cDNA level and p.Leu1679Ter (L1679X) at the protein level. The normal sequence, with the base that is deleted in brackets, is TTAT[C]TAAT. The deletion causes a frameshift resulting in a nonsense variant, which changes a Leucine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.5035delC, also published as BRCA1 c.5154delC using alternate nomenclature, has been observed in cases of familial breast cancer (Juwle 2012, Manguoglu 2010).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000112469	SCV000296459	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-23	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000238807	SCV000296804	pathogenic	not specified	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112469	SCV000326114	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000582738	SCV000688533	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 16 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 individuals and families affected with breast and ovarian cancer (PMID: 21156238, 22752604, 22874498, 26911350, 27553291, 31528241, 33629534, 35377489). 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	RCV001386105	SCV001586211	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1679*) 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). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 21156238, 22752604, 22874498, 26911350). This variant is also known as 5154delC. ClinVar contains an entry for this variant (Variation ID: 55358). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000112469	SCV002003977	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000497274	SCV002024645	pathogenic	not provided	2021-09-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582738	SCV003911983	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-29	criteria provided, single submitter	clinical testing	The c.5035delC pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5035, causing a translational frameshift with a predicted alternate stop codon (p.L1679*). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620). Specifically, this variant has been reported in Indian and Pakistani patients with breast and/or ovarian cancer and is a proposed founder mutation (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Rashid MU et al. Hered Cancer Clin Pract, 2019 Sep;17:27; Sunar V et al. Asia Pac J Clin Oncol, 2022 Feb;18:84-92; Rashid MU et al. Int J Cancer, 2022 Aug;151:402-411). Of note, this variant is also designated as 5154del in published literature. 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112469	SCV000145269	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112469	SCV000297617	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-11-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000497274	SCV000591563	uncertain significance	not provided		no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112469	SCV003927195	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A known pathogenic mutation was detected in the BRCA1 gene (c.5098delC) This sequence change creates a premature translational stop signal (p.Leu1700*) 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). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 21156238, 22752604, 22874498, 26911350). This variant is also known as 5154delC, and c.5035del. ClinVar contains an entry for this variant (Variation ID: 55358) with 12 submissions. Therefore, this variant has been classified as Pathogenic. This variant was confirmed by Sanger sequencing.