Submissions for variant NM_032043.3(BRIP1):c.1628+5G>A

dbSNP: rs754929230

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557392	SCV000633564	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754929230, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 461078). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000572734	SCV000668875	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The c.1628+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the BRIP1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000572734	SCV000684145	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-30	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 11 of the BRIP1 gene. A study using RNA from carrier-derived cells has reported that this variant leads to the skipping of exon 11, creating a premature translation stop signal in the RNA transcript (Leiden Open Variation Database (LOVD) variant number: 0000115868). The aberrant transcript is expected to result in an absent or non-functional protein product. Abnormal RNA splicing resulting from this variant has also been reported in ClinVar (ClinVar variation ID: 461078; communication with an external laboratory). This variant has been reported in individuals affected with ovarian cancer or breast cancer (LOVD; Color internal data). This variant has been identified in 1/251154 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 Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701622	SCV000699671	uncertain significance	not specified	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1628+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by published functional studies. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1628+5G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 461078). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000586595	SCV001843509	likely pathogenic	not provided	2024-02-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003459210	SCV004217067	likely pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000586595	SCV001364527	pathogenic	not provided	2016-06-11	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Andreas Laner.
Revvity Omics, Revvity	RCV003144327	SCV003830166	uncertain significance	Fanconi anemia complementation group J	2021-09-28	flagged submission	clinical testing