Submissions for variant NM_032043.3(BRIP1):c.917dup (p.Asn306fs)

dbSNP: rs1555609121

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000571540	SCV000661562	pathogenic	Hereditary cancer-predisposing syndrome	2016-10-12	criteria provided, single submitter	clinical testing	The c.917dupA pathogenic mutation, located in coding exon 6 of the BRIP1 gene, results from a duplication of A at nucleotide position 917, causing a translational frameshift with a predicted alternate stop codon. 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.
GeneDx	RCV000657409	SCV000779144	likely pathogenic	not provided	2017-11-06	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRIP1 is denoted c.917dupA at the cDNA level and p.Asn306LysfsX13 (N306KfsX13) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAA[dupA]GTGA. The duplication causes a frameshift which changes an Asparagine to a Lysine at codon 306, and creates a premature stop codon at position 13 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767098	SCV004585939	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn306Lysfs*13) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 33558524). ClinVar contains an entry for this variant (Variation ID: 479450). For these reasons, this variant has been classified as Pathogenic.
Center of Medical Genetics and Primary Health Care	RCV001005049	SCV000987301	pathogenic	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRIP1 gene pathogenic variant Asn306Lysfs is in exon 7 in the DEAD_2 domain (F248-415L aa) and in a mutation hotspot of 9 pathogenic variants (PM1 Pathogenic Moderate). This represents a conserved region within a number of RAD3-like DNA-binding helicases that are seemingly ubiquitous– members include proteins of eukaryotic, bacterial and archaeal origin. RAD3 is involved in nucleotide excision repair, and forms part of the transcription factor TFIIH in yeast. This deleterious frame shift mutation distroys the downstream BRCA1 binding domain which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). This variant is reported in ClinVar as a pathogenic or a likely pathogenic variant. In our study it was found in a 59-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic.