Submissions for variant NM_000059.4(BRCA2):c.9117G>T (p.Pro3039=)

dbSNP: rs28897756

Total submissions: 3

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	RCV000258500	SCV000328058	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227101	SCV001399440	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not 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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer, ovarian cancer, or melanoma (PMID: 29446198, 29470806, 33077847). ClinVar contains an entry for this variant (Variation ID: 267715). 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 23 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.9117 nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10638982, 17011978, 22632462, 23451180). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001227101	SCV001519485	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9117G>T (p.Pro3039Pro) alters a conserved nucleotide located at the last nucleotide of exon 23 adjacent to a canonical 5' splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. RNA analysis performed at our partner laboratory indicates that this variant induces altered splicing and may result in an absent or disrupted protein product due to skipping of exon 23 which introduces a premature termination codon (Internal data). The resulting mRNA is expected to undergo nonsense-mediated decay. The variant was absent in 248378 control chromosomes. c.9117G>T has been reported in the literature in at-least two individuals affected with familial breast cancer (example, Rebbeck_2018, Singh_2018). Of note, a different nucleotide change, c.9117G>A, resulting in the same synonymous alteration (p.Pro3039Pro) has been widely reported among individuals/families with breast cancer worldwide (example, Rebbeck_2018) and has been classified as pathogenic by our laboratory. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29446198, 29470806, Internal data). ClinVar contains an entry for this variant (Variation ID: 267715). Based on the evidence outlined above, the variant was classified as likely pathogenic.