Submissions for variant NM_007294.4(BRCA1):c.4625_4626del (p.Ser1542fs)

dbSNP: rs80357542

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112367	SCV000300148	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	RCV000236865	SCV000293464	pathogenic	not provided	2016-02-24	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in BRCA1 is denoted c.4625_4626delCT at the cDNA level and p.Ser1542TrpfsX31 (S1542WfsX31) at the protein level. The normal sequence, with the bases that are deleted in braces, is GAGT[CT]GGGC. The deletion causes a frameshift which changes a Serine to a Tryptophan at codon 1542, and creates a premature stop codon at position 31 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.4625_4626delCT has been observed in at least two breast/ovarian cancer families (Evans 2003). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112367	SCV000326012	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022804	SCV001184582	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-13	criteria provided, single submitter	clinical testing	The c.4625_4626delCT pathogenic mutation, located in coding exon 13 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4625 to 4626, causing a translational frameshift with a predicted alternate stop codon (p.S1542Wfs*31). This mutation has been reported in multiple probands with hereditary breast and/or ovarian cancer (Evans DG et al. J. Med. Genet., 2003 Sep;40:e107; Palmero EI et al. Sci Rep, 2018 Jun;8:9188). Of note, this mutation is also designated as 4744delCT in published literature. In addition to the clinical data presented in the liaterature, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382845	SCV001581792	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1542Trpfs*31) 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 variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is also known as 4744delCT. ClinVar contains an entry for this variant (Variation ID: 55243). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504946	SCV002799511	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-02-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001022804	SCV004360163	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 14 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 detected in 2 suspected hereditary breast and ovarian cancer families (PMID: 12960223). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001382845	SCV004847912	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Ser1542TrpfsX31 variant in BRCA1 has been reported in at least 6 individuals with hereditary breast and/or ovarian cancer (HBOC; Evans 2003, BIC database) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1542 and leads to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55243). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112367	SCV000145133	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000112367	SCV000591528	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The p.Ser1542TrpfsX31 deletion variant was identified by Evans (2003) in 2 families with breast or ovarian cancer. The variant was also identified in dbSNP (ID: rs80357542) “With pathogenic allele”, HGMD, the BIC database (4X as a clinically important variant), and in the ClinVar database (submitted by BIC). The p.Ser1542TrpfsX31 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1542 and leads to a premature stop codon 31 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.