Submissions for variant NM_000059.4(BRCA2):c.68-7del

dbSNP: rs276174878

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566831	SCV004101435	benign	BRCA2-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.68-7del variant is an intronic variant occurring in intron 2 of the BRCA2 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 0.00002293 in the Latino/Admixed American population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to <= 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA2 intronic variant is outside of the native donor and acceptor 1,2 splice sites, and SpliceAI predictor score of 0.04 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is an intronic variant, and mRNA experimental analysis indicates no impact on splicing (PMIDs: 10534775, 21673748, 22505045), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 35979650) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.32 (based on Pathology LR=0.32), within the thresholds for Supporting benign evidence (LR 0.23-0.48) (BP5 met; PMID: 35979650). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP4, BP7_Strong (RNA), BS3, BP5).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045052	SCV000073065	benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045052	SCV000267840	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000496763	SCV000588066	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580115	SCV000683811	benign	Hereditary cancer-predisposing syndrome	2016-09-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001705701	SCV001914534	benign	not provided	2019-01-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10023017, 10451700, 17333343, 10534775)
Sema4, Sema4	RCV000580115	SCV002536277	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	curation
Ambry Genetics	RCV000580115	SCV002665099	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000496763	SCV004242616	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000045052	SCV005184351	benign	Hereditary breast ovarian cancer syndrome	2024-05-03	criteria provided, single submitter	curation	In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP4, BP7_Strong (RNA), BS3, BP5) see entry by ENIGMA for details; According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: BP4 (supporting benign): ENIGMA, BP5 (supporting benign): ENIGMA, BP7 (strong benign): ENIGMA, BS1 (supporting benign): ENIGMA, BS3 (strong benign): ENIGMA
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113085	SCV000146101	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing