Submissions for variant NM_000059.4(BRCA2):c.9502-12T>G (rs81002803)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114123	SCV001161603	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 = 4.00E-07
Invitae	RCV000045842	SCV000073855	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131584	SCV000186594	likely benign	Hereditary cancer-predisposing syndrome	2014-06-05	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
GeneDx	RCV000589086	SCV000210509	uncertain significance	not provided	2018-11-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9502-12T>G or IVS25-12T>G and consists of a T>G nucleotide substitution at the -12 position of intron 25 of the BRCA2 gene. In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. While an mRNA analysis suggested this variant causes loss of the nearby splice acceptor site, leading to deletion of exon 26 and a non-functional protein (Joosse 2012), an RT-PCR mini-gene assay detected only weak effects on splicing (Acedo 2015). This variant, also denoted as 9730-12T>G using alternate nomenclature, has been observed in at least four individuals with a personal or family history of breast and/or ovarian cancer (Vehmanen 1997, Levanat 2012, Tea 2014, Wong-Brown 2015). BRCA2 c.9502-12T>G was also seen in a breast tumor, which was determined to have characteristics similar to BRCA2-associated tumors (Joosse 2012). This variant was observed at an allele frequency of 0.02% (28/126,428) in individuals of European ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA2 c.9502-12T>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina	RCV000114123	SCV000383803	uncertain significance	Breast-ovarian cancer, familial 2	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000160171	SCV000592291	uncertain significance	not specified	2015-03-27	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000589086	SCV000695247	likely benign	not provided	2016-08-31	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9502-12T>G variant affects a non-conserved nucleotide, resulting in an intronic change. 5/5 in silico tools via Alamut predict a weakening effect on the RNA splicing acceptor site and 2/5 in silico tools predict a gain of a cryptic RNA splicing donor site. ESEfinder predicts gain of binding motifs for RNA splicing enhancers. However, the variant was shown through transcription assays to have little effect on splicing by two independent research groups (Houdayer_BRCA1&2_HM_2012, Acedo_HM_2015). Two other studies stated that variant of interest led to the deletion of exon 26 (Joosse_Breast Cancer Res Treat_2012 and Wong-Brown_BRCA1&2_BCRT_2015) without any experimental evidence given. This variant was found in 15/121598 control chromosomes at a frequency of 0.0001234, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0007503). This variant has been reported in multiple affected individuals without strong evidence for causality. However, a reputable database cites the variant to co-occur with another pathogenic BRCA2 variant, c.1232_1242delinsACAT (p.Ile411AsnfsX17). In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign/benign" or "uncertain significance." Therefore, the variant of interest has been classified as Likely Benign.
Mendelics	RCV000045842	SCV000838907	uncertain significance	Hereditary breast and ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color	RCV000131584	SCV000910621	benign	Hereditary cancer-predisposing syndrome	2016-04-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000114123	SCV001139267	uncertain significance	Breast-ovarian cancer, familial 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001110141	SCV001267540	uncertain significance	Fanconi anemia, complementation group D1	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114123	SCV000147656	benign	Breast-ovarian cancer, familial 2	1999-06-21	no assertion criteria provided	clinical testing