Submissions for variant NM_000059.4(BRCA2):c.9501+9A>C

gnomAD frequency: 0.00011  dbSNP: rs81002867

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031826	SCV001161627	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000013
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203671	SCV000073853	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000045840	SCV000210688	benign	not specified	2014-08-07	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.
Counsyl	RCV000031826	SCV000220564	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-31	criteria provided, single submitter	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045840	SCV000602802	benign	not specified	2016-10-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580804	SCV000684067	benign	Hereditary cancer-predisposing syndrome	2015-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587709	SCV000695246	benign	not provided	2016-04-07	criteria provided, single submitter	clinical testing	Variant Summary: The c.9501+9A>C variant is a BRCA2 intronic variant located at a position not widely known to affect splicing. 4/5 splicing prediction programs (via Alamut) suggest no significant effect on splicing, ESE finder predicts no change to binding motifs, and Mutation Taster predicts the variant to be a polymorphism. The observed allele frequency in controls including the large and diverse ExAC cohort is 4/121488(1/30372), which does not exceed the maximal expected alelle frequency for a pathogenic BRCA2 variant (1/1333). However, it has been reported to co-occur with several potentially pathogenic variant in BRCA2 (c.5909C>A, p.Ser1970X - UMD; BRCA2 c.5410_5411delGT (p.Val1804Lysfs) - BIC; BRCA2 c.9382C>T (p.Arg3128Ter) - BIC and BRCA1 IVS3+3A>C (Claes_2003). In addition, multiple reputable databases/clinical diagnostic labs (UMD, GeneDx, and SCRP) and publications (Lindor_2012 and Easton_2007) classify the variant as benign/neutral. Furthermore, functional studies from multiple independent publications report that the variant of interest does not affect splicing (Campos_2003, Claes_2003, Houdayer_2012, and Whiley_2011). Taken together, this BRCA2 intronic variant has been classified as Benign.
Mendelics	RCV000031826	SCV001139265	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110140	SCV001267538	likely benign	Fanconi anemia complementation group D1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000031826	SCV001267539	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sema4, Sema4	RCV000580804	SCV002532039	likely benign	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000045840	SCV002551852	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031826	SCV000054434	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-10-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031826	SCV000147654	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000203671	SCV000916377	benign	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357334	SCV001552777	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 c.9501+9A>C variant was identified in 1 of 820 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian (Diez 2003) and was not identified in 200 control chromosomes from healthy individuals (Claes 2003). The variant was also identified in dbSNP (ID: rs81002867) as With other allele, ClinVar (classified as benign by GeneDx, ARUP, Color Genomics, Laboratory Corporation of America, Invitae, SCRP; as likely benign by Counsyl), Clinvitae, COGR (likely benign/benign), LOVD 3.0, UMD-LSDB (36X uncertain significance), BIC Database (unknown clinical importance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.5909C>A (p.Ser1970X), increasing the likelihood that the c.9501+9A>C variant does not have clinical significance. The variant was not identified in ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 17 of 276704 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 6454 chromosomes (freq: 0.0002), Latino in 3 of 34398 chromosomes (freq: 0.0001), European in 13 of 126364 chromosomes (freq: 0.0001); but not in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, mRNA and bioinformatics analysis of the variant showed no alteration effect at the cDNA and protein level (Easton 2007, Campos 2003, Claes 2003, Houdayer 2012, Lindor 2012, Whiley 2011, Thery 2011). 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	RCV004532470	SCV004754496	likely benign	BRCA2-related disorder	2019-06-19	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).