Submissions for variant NM_032043.3(BRIP1):c.141del (p.Thr48fs)

dbSNP: rs587782065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130549	SCV000185418	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	clinical testing	The c.141delC pathogenic mutation, located in coding exon 2 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 141, causing a translational frameshift with a predicted alternate stop codon (p.T48Qfs*7). This mutation was detected in 1/1212 women diagnosed with breast cancer and was not detected in 2081 controls (Seal S et al. Nat. Genet. 2006; 38:1239-41). 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	RCV000536840	SCV000633502	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr48Glnfs*7) 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 chondrosarcoma and a personal and family history of breast cancer (PMID: 17033622, 26556299). ClinVar contains an entry for this variant (Variation ID: 141861). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657235	SCV000778961	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in a patient with breast cancer (PMID: 17033622); Published functional studies demonstrate reduced homologous recombination activity (PMID: 33032822); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20346647, 19763819, 28152038, 26556299, 16116423, 21964575, 23242139, 33032822, 17033622)
Color Diagnostics, LLC DBA Color Health	RCV000130549	SCV000905215	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 3 of the BRIP1 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 not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174940	SCV001338391	likely pathogenic	Familial cancer of breast	2020-02-25	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.141delC (p.Thr48GlnfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251412 control chromosomes (gnomAD). c.141delC has been reported in the literature in at least one individual with a personal- and family history of breast cancer (Seal_2006, Ruark_2013) and one individual affected with chondrosarcoma (Schrader_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000536840	SCV002795368	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2022-04-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001174940	SCV004045513	pathogenic	Familial cancer of breast	2023-05-30	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV001174940	SCV004214669	pathogenic	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing