Submissions for variant NM_000059.4(BRCA2):c.8632+2T>C

dbSNP: rs397507998

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001963311	SCV002241587	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 20 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered 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 breast and/or ovarian cancer (PMID: 28975465, 30199306). This variant is also known as c.8633+2T>C. ClinVar contains an entry for this variant (Variation ID: 1460449). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Studies have shown that disruption of this splice site results in skipping of exon 20, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 24212087, 29774201, 30101128, 30623411). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003475260	SCV004210533	pathogenic	Familial cancer of breast	2022-07-23	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003991046	SCV004808361	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-04-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 20 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or 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 breast and/or ovarian cancer (PMID: 28975465, 30199306). This variant is also known as c.8633+2T>C. ClinVar contains an entry for this variant (Variation ID: 1460449). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Studies have shown that disruption of this splice site results in skipping of exon 20 and introduces a premature termination codon (PMID: 24212087, 29774201, 30101128, 30623411). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004946942	SCV005552911	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-29	criteria provided, single submitter	clinical testing	The c.8632+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 19 in the BRCA2 gene. This variant was detected in 1/310 patients with breast cancer and at least one high-risk criteria (Abulkhair O et al. J Glob Oncol, 2018 Aug;4:1-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however direct evidence is insufficient at this time. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). Based on the available evidence, the clinical significance of this alteration remains unclear.