ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.301+7G>A

gnomAD frequency: 0.00006  dbSNP: rs80358113
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV000031080 SCV004101420 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-10-10 reviewed by expert panel curation The c.301+7G>A variant is an intronic variant occurring in intron 5 of the BRCA1 gene. The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.00009711 in the European (non-Finnish) population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to <= 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.21, predicting an impact on splicing (score threshold >0.20) (however, this prediction is to strengthen the native acceptor site and therefore PP3 is not applied). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMID: 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 30209399) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 4.848E-11 (based on Cosegregation LR=1.36; Pathology LR=0.001; Co-occurrence LR=0.068; Family History LR=0.037; Case-Control LR=1.28E-05), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP7_Strong (RNA), BS3, BP5_Very strong).
GeneDx RCV000168481 SCV000209904 benign not specified 2014-06-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001086785 SCV000252814 benign Hereditary breast ovarian cancer syndrome 2024-01-31 criteria provided, single submitter clinical testing
Counsyl RCV000031080 SCV000488102 benign Breast-ovarian cancer, familial, susceptibility to, 1 2015-12-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000579925 SCV000683078 likely benign Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759515 SCV000888882 benign not provided 2022-09-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168481 SCV000918797 benign not specified 2021-07-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.301+7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. At least two publication reports experimental evidence evaluating an impact on splicing. These results showed no damaging effect of this variant (Steffensen_2014, Houdayer_2012). The variant allele was found at a frequency of 9.5e-05 in 251608 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (9.5e-05 vs 0.001), allowing no conclusion about variant significance. c.301+7G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Konstantopoulou_2008, Ratajska_2014, Kluska_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (4x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen RCV000759515 SCV001151341 benign not provided 2024-04-01 criteria provided, single submitter clinical testing BRCA1: BP4, BS1, BS2
Genetic Services Laboratory, University of Chicago RCV000168481 SCV002072390 likely benign not specified 2019-04-23 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000579925 SCV002538168 likely benign Hereditary cancer-predisposing syndrome 2021-04-11 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000168481 SCV002551062 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000579925 SCV002753294 benign Hereditary cancer-predisposing syndrome 2014-11-18 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.
Sharing Clinical Reports Project (SCRP) RCV000031080 SCV000053676 benign Breast-ovarian cancer, familial, susceptibility to, 1 2011-03-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031080 SCV000144958 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000031080 SCV001238612 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
BRCAlab, Lund University RCV000031080 SCV004244178 benign Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing

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