Submissions for variant NM_007294.4(BRCA1):c.1952del (p.Lys651fs)

dbSNP: rs80357885

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241429	SCV000299671	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	RCV000074568	SCV000108653	pathogenic	Familial cancer of breast	2013-11-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1952delA at the cDNA level or p.Lys651ArgfsX50 (K651RfsX50) at the protein level. The surrounding sequence is: ATAA{delA}GAAA. The deletion is a frameshift mutation, changing a Lysine residue to an Arginine residue at codon 651, and creating a premature stop codon at position 50 of the new reading frame. BRCA1 c.1952delA is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This deletion, denoted as 2069delA in the following publication using alternative nomenclature, has been reported in association with familial breast and ovarian cancer (Stoppa-Lyonet 1997). and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA1-related cancer risks for women who have not been diagnosed with cancer have been estimated to be 57% - 84% lifetime risk for breast cancer and 24% - 54% lifetime risk for ovarian cancer (Antoniou 2003, Chen 2007, Ford 1998). BRCA1 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Pennington 2013). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA1 mutation include approximately 3% risk for pancreatic cancer (The Breast Cancer Linkage Consortium 1999), a 20% risk for prostate cancer (Thompson 2002), and 4% risk for male breast cancer (Liede 2004). The variant is found in BRCA1-BRCA2 panel(s).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241429	SCV000325194	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043327	SCV001207060	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys651Argfs*50) 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 personal and/or family history of breast and/or ovarian cancer (PMID: 9150149). This variant is also known as 2069delA. ClinVar contains an entry for this variant (Variation ID: 54410). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003584528	SCV004361042	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This variant deletes 1 basepair in exon 10 in the BRCA1 gene, creating a premature translation termination codon. This variant is expected to cause an absent or non-functional protein product. This variant has been reported in a family with members affected with breast cancer and both breast and ovarian cancer (PMID: 9150149). 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.