Submissions for variant NM_000059.4(BRCA2):c.476-3C>A

gnomAD frequency: 0.00004  dbSNP: rs371431745

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224376	SCV001396566	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs371431745, gnomAD 0.05%). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 27062684, 29446198, 30078507, 30630526, 34026625, 35641994). ClinVar contains an entry for this variant (Variation ID: 37924). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 30832263, 30883759; internal data). 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.
Ambry Genetics	RCV002336101	SCV002635624	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-06	criteria provided, single submitter	clinical testing	The c.476-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 5 in the BRCA2 gene. This alteration has been observed in multiple individuals and families with high risk breast and ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Li A et al. Gynecol Oncol, 2018 10;151:145-152). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated this alteration results in an incomplete splicing in the set of samples tested; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data; Gelli E et al. Cancers (Basel), 2019 Mar;11; Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003460513	SCV004213704	uncertain significance	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002336101	SCV004361172	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-09	criteria provided, single submitter	clinical testing	This variant causes a C to A nucleotide substitution at the -3 position of intron 5 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported that this variant is detected with increased out-of-frame splicing predicted to cause premature truncation and an absent or non-functional protein product, albeit the splicing defect may be incomplete (PMID: 30832263, 30883759). This variant has been reported in at least two individuals affected with breast or ovarian cancer and in additional families affected with hereditary breast and ovarian cancer (PMID: 27062684, 29446198, 30078507, 30630526). This variant also has been reported in an individual diagnosed with Fanconi anemia with a pathogenic BRCA2 co-variant (PMID: 27862952). By contrast, this variant is not considered rare and has been identified in 12/282210 chromosomes (12/267726 chromosomes in the non-cancer cohort) in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease and perhaps being less penetrant than a classic loss-of-function mutation in the BRCA2 gene, additional case-control and functional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
MGZ Medical Genetics Center	RCV003460513	SCV004543895	uncertain significance	Familial cancer of breast	2024-06-10	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: PP3
Sharing Clinical Reports Project (SCRP)	RCV000031505	SCV000054110	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-07-11	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031505	SCV004228419	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PP3(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)