ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9501+9A>C (rs81002867)

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Total submissions: 14
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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 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
Invitae RCV000203671 SCV000073853 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 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 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 Health, Inc 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 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000031826 SCV001267539 likely benign Breast-ovarian cancer, familial 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.
Sharing Clinical Reports Project (SCRP) RCV000031826 SCV000054434 benign Breast-ovarian cancer, familial 2 2008-10-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031826 SCV000147654 uncertain significance Breast-ovarian cancer, familial 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 and 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.

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