Submissions for variant NM_032043.3(BRIP1):c.2273dup (p.Ala759fs)

gnomAD frequency: 0.00001  dbSNP: rs587780236

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000258967	SCV000150047	pathogenic	not provided	2022-08-22	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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 29922827, 27433846, 27806231, 29368626, 29625052, 32359370)
Ambry Genetics	RCV000116138	SCV000216196	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	clinical testing	The c.2273dupT pathogenic mutation, located in coding exon 15 of the BRIP1 gene, results from a duplication of T at nucleotide position 2273, causing a translational frameshift with a predicted alternate stop codon (p.A759Sfs*6). This alteration has been identified in individuals diagnosed with breast, ovarian and/or prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Weber-Lassalle N et al. Breast Cancer Res, 2018 01;20:7; Dorling et al. N Engl J Med. 2021 02;384:428-43) and in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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.
Counsyl	RCV000576781	SCV000677798	likely pathogenic	Fanconi anemia complementation group J; Neoplasm of ovary	2016-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV000636094	SCV000757526	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala759Serfs*6) 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 present in population databases (rs587780236, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 26681312, 27433846, 29368626). ClinVar contains an entry for this variant (Variation ID: 128170). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000116138	SCV000911175	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 16 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 been identified in 2/251216 chromosomes 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.
CeGaT Center for Human Genetics Tuebingen	RCV000258967	SCV001248139	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193525	SCV001362420	pathogenic	Familial cancer of breast	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2273dupT (p.Ala759SerfsX6) 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 (c.2392C>T, p.Arg798X; c.2400C>G, p.Tyr800X). The variant allele was found at a frequency of 8e-06 in 251216 control chromosomes (gnomAD). c.2273dupT has been reported in the literature in individuals affected with endometrial, prostate, ovarian or breast cancer (Susswein_2016, Pritchard_2016, Weber-Lassalle_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV001193525	SCV002581013	pathogenic	Familial cancer of breast	2022-06-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001193525	SCV004019511	pathogenic	Familial cancer of breast	2023-03-02	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	RCV001193525	SCV004214783	pathogenic	Familial cancer of breast	2023-08-25	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV001193525	SCV004803219	pathogenic	Familial cancer of breast	2024-03-06	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM2, PP4, PP5; Variant was found in heterozygous state
Leiden Open Variation Database	RCV000258967	SCV001364467	likely pathogenic	not provided	2019-12-04	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Andreas Laner.