Submissions for variant NM_007294.4(BRCA1):c.5468-2A>G

dbSNP: rs398122699

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077170	SCV000326324	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637422	SCV000758879	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-27	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91653). This sequence change affects an acceptor splice site in intron 22 of the BRCA1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary breast and ovarian cancer syndrome (PMID: 26028024). In at least one individual the variant was observed to be de novo.
Ambry Genetics	RCV001024146	SCV001186114	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-19	criteria provided, single submitter	clinical testing	The c.5468-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 22 in the BRCA1 gene. This alteration has been reported in multiple individuals from a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations (Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). It has also been reported as a de novo alteration in an individual with ovarian cancer at age 39, however it is it unclear if paternity was confirmed in this study (Golmard L et al. Oncogene, 2016 Mar;35:1324-7). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A close match alteration at this acceptor site, BRCA1 c.5468-1G>A was shown to make use of a cryptic acceptor site 11nt downstream (Baert A et al. Hum. Mutat., 2018 04;39:515-526). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077170	SCV000108967	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-11-09	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077170	SCV001243978	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077170	SCV001549736	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 c.5468-2A>G variant was identified in 3 of 83182 proband chromosomes (frequency: 0.00004) from individuals or families with breast or ovarian cancer (Golmard 2016, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs398122699) as "With Pathogenic, other allele", in ClinVar (classified as pathogenic by CIMBA; as likely pathogenic by Invitae and SCRP), and in LOVD 3.0 (2x as pathogenic). The variant was not identified in UMD-LSDB, database. The variant was not identified in the Genome Aggregation Database (Feb 27, 2017). The c.5468-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
BRCAlab, Lund University	RCV000077170	SCV002588840	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing