ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8954-5_8954-2del

dbSNP: rs587782878
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132512 SCV000187608 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV001081516 SCV000261842 benign Hereditary breast ovarian cancer syndrome 2024-01-27 criteria provided, single submitter clinical testing
Counsyl RCV000031782 SCV000487807 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2015-11-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000132512 SCV000684011 benign Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000204559 SCV001133959 benign not provided 2023-06-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000503174 SCV001361753 benign not specified 2019-05-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8954-5_8954-2delAACA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 281868 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.8954-5_8954-2delAACA, has been reported in the literature in individuals affected with breast cancer but without evidence for causality (Carney_2010, Chan_2018, Lai_2017, Suter_2004). In addition, co-occurrences with pathogenic BRCA2 variant have been reported (c.7878G>A, p.Trp2626X; Carney_2010, LabCorp internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=2), Benign (n=2)). Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV000204559 SCV001945433 benign not provided 2015-07-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 31825140)
Sema4, Sema4 RCV000132512 SCV002531992 likely benign Hereditary cancer-predisposing syndrome 2021-12-06 criteria provided, single submitter curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003492319 SCV004240371 likely benign Breast and/or ovarian cancer 2022-09-20 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000031782 SCV004809643 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2024-04-04 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000503174 SCV005090071 likely benign not specified 2024-07-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031782 SCV000054390 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2011-03-04 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353794 SCV000592243 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 c.8954-5_8954-2delAACA was identified in the literature in an individual with breast cancer. However in the same patient a co-occurring pathogenic BRCA2 variant (p.Trp2626X) was identified, increasing the likelihood that the c.8954-5_8954-2delAACA variant may not have clinical significance (Carney 2010). The variant was also identified in the Clinvar database (classified as likely benign by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports); classified as likely benign by Ambry Genetics). The c.8954-5_8954-2delAACA variant occurs within the invariant dinucleotide AG sequence (at positions -2 to -1) within the 3’ splice region. Although the deletion affects the -2 nucleotide (adenine, or A), the four base-pair deletion (AACA) results in a sequence with an adenine (A) at the -2 position, thus preserving the invariant AG donor sequence. Positions -3 and -5 to 12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant sequence resulting from the 4 base-pair deletion is different from the wild-type sequence within this region, thus splicing may be affected. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a change to the donor splice site; however this information is not predictive enough to rule out pathogenicity.In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences RCV004541051 SCV004770388 likely benign BRCA2-related disorder 2023-09-11 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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