Submissions for variant NM_007294.4(BRCA1):c.1508del (p.Lys503fs)

dbSNP: rs80357506

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111634	SCV000299610	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111634	SCV000325087	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484870	SCV000569659	pathogenic	not provided	2018-06-27	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.1508delA at the cDNA level and p.Lys503SerfsX29 (K503SfsX29) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 1627delA. The normal sequence, with the base that is deleted in brackets, is TTAA[delA]GCGT. The deletion causes a frameshift which changes a Lysine to a Serine at codon 503, and creates a premature stop codon at position 29 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.1508delA has been reported in at least one individual from a hereditary breast/ovarian cancer family (Judkins 2005). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502143	SCV000698869	pathogenic	Hereditary breast ovarian cancer syndrome	2016-03-08	criteria provided, single submitter	clinical testing	Variant summary: This c.1508delA variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 503 and leads to a premature termination codon 29 amino acids downstream. It is predicted to cause a truncated or absent BRCA1 protein. Loss-of-function due to mutations in this gene is an established disease mechanism in HBOC. This variant was not found in 121212 control chromosomes from ExAC but is reported in two individuals affected with HBOC or HBOC-related cancer. One reputable database has classified this variant as pathogenic. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln563X, p.Lys654X, p.Ser713X, etc.). Taken together, this variant been classified as pathogenic.
Ambry Genetics	RCV002390198	SCV002699455	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-24	criteria provided, single submitter	clinical testing	The c.1508delA variant, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at position 1508, causing a translational frameshift with a predicted alternate stop codon (p.K503Sfs*29). This alteration was identified in a large, worldwide study of BRCA1 and BRCA2 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.
Invitae	RCV000502143	SCV003497945	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys503Serfs*29) 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/or ovarian cancer (PMID: 36169650). ClinVar contains an entry for this variant (Variation ID: 54275). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV002390198	SCV004361057	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-08	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, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111634	SCV000144116	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353743	SCV000591338	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Lys503SerfsX29 deletion variant was identified in the literature in at least one proband from a large cohort of patients tested for BRCA1 and BRCA2 mutations at Myriad Genetics Laboratories (Judkins 2005). The variant was identified in the dbSNP database (ID: rs80357506) “With pathogenic allele”, the BIC databsase (1X, classified as pathogenic), and in the ClinVar database with submissions by BIC and Invitae (classification not provided). The p.Lys503SerfsX29 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 503 and leads to a premature stop codon 29 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.