Submissions for variant NM_000059.4(BRCA2):c.9501+1G>A

dbSNP: rs397508058

Total submissions: 8

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	RCV000258387	SCV000328146	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000585647	SCV000693550	likely pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a substitution of the first nucleotide base of intron 25 of the BRCA2 gene. This position is conserved in the human and other genomes and might be involved in mRNA processing. Therefore, this variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The mutation database ClinVar contains entries for this variant (Variation ID: 52853).
CeGaT Center for Human Genetics Tuebingen	RCV001092812	SCV001249503	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189741	SCV001357099	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 25 of the BRCA2 gene. An RNA study has shown that this variant causes the out-of-frame skipping of exon 25, resulting in premature truncation, in the analysis of RNA from two carriers (PMID: 29310832). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in individuals affected with breast and/or ovarian cancer (PMID: 29310832, 30720863, 32963034; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852966	SCV002288495	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-06-10	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 25 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 cancer (PMID: 29310832, 30720863, 31209999, 34645131). ClinVar contains an entry for this variant (Variation ID: 52853). Studies have shown that disruption of this splice site results in skipping of exon 25 and introduces a premature termination codon (PMID: 29310832). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics	RCV001189741	SCV002686992	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The c.9501+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 24 of the BRCA2 gene. This mutation has been detected in multiple Greek women with a personal history of breast cancer diagnosed before age 40 (Apessos A et al. Cancer Genet, 2018 01;220:1-12; Fostira F et al. J Med Genet, 2020 01;57:53-61). This mutation was also detected in 1/2769 Chinese breast cancer patients (Deng M et al. Int J Cancer, 2019 09;145:1517-1528). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001092812	SCV005196955	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000258387	SCV005627762	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 25 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 position is conserved in the human. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 29310832, 30720863, 31209999, 34645131). ClinVar contains an entry for this variant (Variation ID: 52853). Studies have shown that disruption of this splice site results in skipping of exon 25 and introduces a premature termination codon (PMID: 29310832). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.