ClinVar Miner

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

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Total submissions: 12
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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) 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 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131584 SCV000186594 likely benign Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing RNA Studies;Subpopulation frequency in support of benign classification
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001358665 SCV000695247 benign not specified 2021-03-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9502-12T>G alters a 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.1e-05 in 251630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (9.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.9502-12T>G has been reported in the literature in individuals affected with breast/ovarian cancer (example, Houdayer_2012, Joosse_2012, Vehmanen_1997, Tea_2014, Levanat_2012, Wong-Brown_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.1232_1242delinsACAT, p.Ile411AsnfsX17), providing supporting evidence for a benign role. Several publications report experimental evidence demonstrating no splicing impact of this variant utilizing stabilized RNA extracted from lymphoblastoid cell lines and in minigene assays (example, Acedo_2015, Houdayer_2012 and Wangensteen_2019). Although at-least one study has demonstrated a partial effect on splicing reporting a skipping of exon 26, the physiological consequences of which are unknown (Leman_2018). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (benign, n=3, likely benign, n=1, VUS, n=5) of whom the expert panel has assessed the variant as benign. Due to the lack of any evidence supporting an actionable outcome in over five years of evaluations at our laboratory, further supported by the emerging consensus among peers as outlined above, the variant was classified as benign.
Mendelics RCV000045842 SCV000838907 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000114123 SCV000592291 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 c.9502-12T>G variant was identified in 4 of 1160 proband chromosomes (frequency: 0.0034) from individuals or families with hereditary breast and ovarian cancer (Joosse 2012, Levanat 2012, Tea 2014). The variant was also identified in dbSNP (ID: rs81002803) as “With Likely benign, Uncertain significance allele,” ClinVar (as Uncertain significance by Ambry Genetics, Likely benign by Invitae and Illumina, and Benign by BIC), Clinvitae (6x), LOVD 3.0 (12x), UMD-LSDB (as likely neutral, co-occurring with a pathogenic variant BRCA2 p.Ile411AsnfsX17), and BIC Database (2x with no clinical importance). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, Zhejiang Colon Cancer Database. The variant was identified in control databases in 33 of 276870 chromosomes at a frequency of 0.000119 (Genome Aggregation Consortium Feb 27, 2017). The variant was also identified by our laboratory in 10 individuals with breast cancer. The literature shows conflicting evidence regarding the pathogenicity of this variant. Based on mRNA studies, the variant has been shown to result in the loss of a splice acceptor site and deletion of exon 26 (Joosse 2012, Vehmanen 1997, Walker 2013). However, another study by Acedo (2015) showed the variant produced weak effects, with less than 15% of abnormal isoforms, thus stating the variants role in breast cancer is questionable but it might constitute a low-penetrance or disease-modifier allele. In addition, statistical analyses by Houdayer (2012) and Pruss (2014) determined that the variant had no splicing effect. The c.9502-12T>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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