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

dbSNP: rs397508058

Total submissions: 5

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	RCV000258166	SCV000328147	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779967	SCV000916932	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9501+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the 5' canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251052 control chromosomes. c.9501+1G>T has been reported in the literature in one unspecified individual who has undertaken BRCA testing (example, Kechin_2020), however no additional information has been provided. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36367610). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic, n=1; likely pathogenic, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779967	SCV000948172	likely pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 25 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29446198, 30720863, 33461583, 34645131, 36367610). ClinVar contains an entry for this variant (Variation ID: 267725). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001019433	SCV001180791	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	The c.9501+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 24 of the BRCA2 gene. 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; however direct evidence is insufficient. 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. As such, this alteration is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800642	SCV002046881	likely pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and is predicted to interfere with normal BRCA2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a Hispanic family with an increased risk of breast and/or ovarian cancer (PMID: 29446198 (2018)). Based on the available information, this variant is classified as likely pathogenic.