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

gnomAD frequency: 0.00006  dbSNP: rs80358113

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566760	SCV004101420	benign	BRCA1-related cancer predisposition	2024-06-11	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086785	SCV000252814	benign	Hereditary breast ovarian cancer syndrome	2025-02-04	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	2025-03-04	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000031080	SCV005398677	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia, complementation group S (MIM#617883), and susceptibility to breast and ovarian cancer (MIM#604370). (I) 0108 - This gene is associated with both recessive and dominant disease. Susceptibility to breast and ovarian cancer follows an autosomal dominant inheritance pattern, while Fanconi anemia is inherited in an autosomal recessive pattern (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. The highest estimate for cancer risk in carriers of pathogenic variants is 80% by the age of 70 years (PMID: 30551077). (I) 0210 - Splice site variant proven not to affect splicing of the transcript. (I) 0304 - Variant is present in gnomAD (v2) <0.001 (22 heterozygotes, 0 homozygotes). (SP) 0805 - This variant has strong previous evidence of being benign. This variant has been reported multiple times as benign or likely benign in the ClinVar database. It has been curated as benign by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (PMID: 31131967). (SB) 1004 - This variant has moderate functional evidence supporting normal function. In vitro RNA studies have shown that this variant does not result in abnormal splicing (PMID: 22505045, 24667779). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357169	SCV005915265	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Fanconi anemia, complementation group S	2021-12-06	criteria provided, single submitter	clinical testing
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
Counsyl	RCV000031080	SCV000488102	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-28	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
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