Submissions for variant NM_032043.3(BRIP1):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs764585550

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167101	SCV000217931	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine at the translation initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however there are alternate in-frame methionines 3 and 27 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000410570	SCV000490065	uncertain significance	Fanconi anemia complementation group J	2016-10-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000411221	SCV000490066	uncertain significance	Ovarian neoplasm	2016-10-27	criteria provided, single submitter	clinical testing
Invitae	RCV000474167	SCV000547365	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the BRIP1 mRNA. The next in-frame methionine is located at codon 4. This variant is present in population databases (rs764585550, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 187378). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000484413	SCV000571262	uncertain significance	not provided	2023-04-18	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which a downstream in-frame ATG could serve as an alternate initiator codon that may result in a functional protein; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 35032816, 32091409)
Color Diagnostics, LLC DBA Color Health	RCV000167101	SCV000904226	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This variant alters the methionine at codon 1 in the BRIP1 protein and is expected to disrupt protein translation initiation. However, in-frame methionines located at codons 4, 28, or 29 could potentially serve as alternate translation start sites. To our knowledge, functional studies have not been performed to determine whether these methionines are utilized for translation initiation. This variant has been reported in individuals affected with breast cancer (PMID: 32091409, 33471991). In an international breast cancer case-control meta-analysis, this variant was detected in 9/60466 cases and 3/53461 unaffected controls (PMID: 33471991; OR=2.653, 95%CI 0.718 to 9.799, p-value=0.155). This variant has been identified in 4/251168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University	RCV002283462	SCV002572489	pathogenic	Genetic non-acquired premature ovarian failure	2021-12-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000474167	SCV002816657	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2021-11-24	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153455	SCV003843588	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing