Submissions for variant NM_007294.4(BRCA1):c.744del (p.Thr249fs)

dbSNP: rs1060502360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661258	SCV000783522	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458382	SCV000549403	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr249Leufs*49) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 409361). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 22160602). This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV000657217	SCV000778943	pathogenic	not provided	2018-02-23	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.744delC at the cDNA level and p.Thr249LeufsX49 (T249LfsX49) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 863delC or 862delC. The normal sequence, with the base that is deleted in brackets, is ACAC[delC]ACTG. The deletion causes a frameshift which changes a Threonine to a Leucine at codon 249, and creates a premature stop codon at position 49 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.744delC has been observed in association with Hereditary Breast and Ovarian Cancer syndrome (Schneegans 2012). We consider this variant to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002481437	SCV002781997	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-05-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000661258	SCV004835408	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-07	criteria provided, single submitter	clinical testing	The c.744del (p.Thr249Leufs*49) variant of the BRCA1 gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in one individual with breast and/or ovarian cancer and positive family history (PMID: 22160602). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.744del (p.Thr249Leufs*49) variant of the BRCA1 gene is classified as pathogenic.
Ambry Genetics	RCV004022724	SCV005026111	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-12	criteria provided, single submitter	clinical testing	The c.744delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 744, causing a translational frameshift with a predicted alternate stop codon (p.T249Lfs*49). 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.