Submissions for variant NM_000059.4(BRCA2):c.475+4del

dbSNP: rs276174848

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569643	SCV000661284	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-26	criteria provided, single submitter	clinical testing	The c.475+4delT intronic variant, located in intron 4 of the BRCA2 gene, results from a deletion of one nucleotide within intron 4 of the BRCA2 gene. This nucleotide position is well conserved in available vertebrate species. This alteration was identified in a Polish individual with a family history and/or personal history of early onset breast and/or ovarian cancer (Kluska A et al. BMC Med Genomics, 2015 May;8:19). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Wai HA et al. Genet Med 2020 06;22(6):1005-1014). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000569643	SCV000688892	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	clinical testing	This variant causes deletion of a T in intron 5 of the BRCA2 gene. Functional studies have shown that this variant resulted in exon 5 skipping and premature truncation (PMID: 32133419). This variant has been reported in individuals affected with breast cancer (PMID: 32133419, 25948282). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001343136	SCV000694800	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.475+4delT alters a non-conserved nucleotide located close to a canonical splice site and therefore it could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site. Publications utilizing patient derived blood RNA samples reported experimental evidence, confirming that this variant affects splicing, resulting in exon 5 skipping with a premature truncation at the protein level (Landrith_2020, Wai_2020). The variant was absent in 251000 control chromosomes (gnomAD). The variant, c.475+4delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (Kluska_2015, Landrith_2020). These data indicate that the variant is likely associated with disease. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001343136	SCV001537100	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-15	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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer, prostate cancer (PMID: 25948282, 32133419). ClinVar contains an entry for this variant (Variation ID: 37921). 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 5, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 32133419; internal data). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000031502	SCV002580847	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000588562	SCV002757323	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Non-canonical splice variant demonstrated to result in out-of-frame exon 5 skipping (Landrith 2020, Wai 2020); Observed in individuals with familial breast/ovarian cancer (Kluska 2015); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 703+4del; This variant is associated with the following publications: (PMID: 32133419, 31131967, 27060066, 32123317, 25948282)
Sharing Clinical Reports Project (SCRP)	RCV000031502	SCV000054107	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031502	SCV000146936	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing