ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4096+3A>G (rs80358015)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164655 SCV000215320 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000031147 SCV000144972 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Cancer Variant Interpretation Group UK,Institute of Cancer Research, London RCV000048442 SCV000897860 likely benign Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data included in classification. Segregation data supporting non-pathogencity, Byrjalsen et al, Clinical case Reports, 2017. Healthy 58y Danish homozygote carrier reported by Byrjalsen et al, Clinical case Reports, 2017 (confirmed on two different genotyping methods). % change MaxEnt Score: -100, % change NNS Score: -98.22845. Alternative splicing reported in Wappenschmidt, B. et al., 2012 PLoS One 7(12). However, variants at c.4096+1 (IVS11+1), c.4096+2 (IVS11+2) are of uncertain pathogenicity on account of rescue by production of naturally occurring in-frame transcripts delta 11q (Bonatti et al., 2006) and also delta 11 (Radice, unpublished data). See ENIGMA classification rules ( Data not included in classification. The variant was observed in 1 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (1/16,600 in familial cases against 0/63,369 GNOMAD NFE controls) pexact= 0.21 2 additional families of Icelandic origin have been tested in the UK. Further cases in Wappenschmidt, B. et al., 2012 PLoS One 7(12): e50800) and Janavicius, R. 2010, EPMA 1(3):397. 5 cases in BIC. 8 reports on ClinVar. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals, but no Icelanders included). Comment. This is a +3 splicing variant which results in alternative splicing but seemingly the impact is mitigated through rescue by alternative functional transcripts. Repeatedly reported in HBOC case, this would appear to be an Icelandic variant; the Icelandic population frequency of this variant is however lacking. The data against segregation and report of a well-phenotyped healthy 58y-old Danish homozygote support this variant being of appreciable population frequency and non-pathogenic.
Department of Medical Genetics,Oslo University Hospital RCV000031147 SCV000564393 uncertain significance Breast-ovarian cancer, familial 1 2017-08-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048442 SCV000591489 pathogenic Hereditary breast and ovarian cancer syndrome 2015-03-27 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031147 SCV000783126 uncertain significance Breast-ovarian cancer, familial 1 2018-04-12 reviewed by expert panel curation Identified in a healthy homozygous carrier at age 58 with a single café au lait spot and a normal chromosomal breakage test (Byrjalsen et al., 2018 - PMID: 28588830). Clinical data collected by the ENIGMA consortium demonstrates that the BRCA1 c.4096+3A>G variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant (Spurdle, unpublished data). This splice site variant has been proven to result in production of naturally occurring in-frame transcripts delta11q and delta11 (Wappenschmidt et al,. 2012 - PMID: 23239986). Since no clinically relevant domain has been described in BRCA1 exon 11 (ENIGMA rules), the splicing alteration is compatible with the clinical data, and supports Class-3 classification.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735547 SCV000863685 pathogenic Breast and/or ovarian cancer 2013-04-13 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765361 SCV000896626 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481455 SCV000568407 uncertain significance not provided 2018-02-07 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4096+3A>G or IVS10+3A>G and consists of an A>G nucleotide substitution at the +3 position of intron 10 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as 4215+3A>G and IVS11+3A>G. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. In line with this prediction, an in vitro RT-PCR study reports that this variant results in transcripts displaying a deletion of 3309 nucleotides from the 3? end of exon 10 and an increase in the naturally occurring BRCA1 deletion exon 10 isoform, also reported as exon 11 using alternate nomenclature, with what appears to be some residual normal transcript production (Wappenschmidt 2012). This variant, also published as 4216nt-2A>G, has been observed in multiple individuals with breast and/or ovarian cancer, and has been reported as a Finnish founder pathogenic variant (Sarantaus 2000, Borg 2010, Beissel 2014, Song 2014). However, Byrjalsen et al. (2017) identified BRCA1 c.4096+3A>G in the homozygous state in a 58 year old healthy female from a consanguineous Danish family thus calling the pathogenicity of this variant into question. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether BRCA1 c.4096+3A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779901 SCV000916803 uncertain significance not specified 2018-09-25 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4096+3A>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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. A functional study confirms that this variant compromises the existing intron 11 donor splice site resulting in a transcript lacking 3309 nucleotides from exon 11 but retaining 117 nucleotides from the 59 end of exon 11, together with increased abundance of the naturally occurring isoforms BRCA1-DELTAex11 (legacy name) (Wappenschmidt_2012). The presence of naturally occurring BRCA1 isoforms lacking exon 11 has recently been described adding to the complexity of assessing the effect of the variant.The variant was absent in 248890 control chromosomes (gnomAD and Song_2014). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4096+3A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Judkins_2005, Song_ 2014, Wappenschmidt_2012, Petersen_2016) and colorectal cancer (Hansen_2017), without strong evidence for pathogenicity in some studies. One study showed lack of segregation with disease for this variant in two individuals from a family with multiple cases of breast and ovarian cancer, including a healthy 58 y/o woman who was homozygous for the variant and a 47 y/o woman with breast cancer who tested negative for this variant (Byrjalsen_2017). In addition, co-occurrences with other pathogenic variants in individuals with a personal history of breast cancer have been reported (BRCA2 c.7007G>A, p.Arg2336His; ATM c.6404_6405insTT, p.Arg2136fsX1), providing supporting evidence for a benign role (Beissel_ 2014, internal testing). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x4, likely pathogenic/pathogenic x2). Based on the conflicting evidence outlined above, the variant was classified as uncertain significance until more functional and family segregation studies become available.
Invitae RCV000048442 SCV000076455 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-04 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families affected with breast and ovarian cancer (PMID: 20104584, 23239986), and observed to segregate with breast cancer in a single family (Invitae). However, it has also been observed as homozygous in a healthy 58-year-old woman from a consanguineous family, whose 87-year-old mother was unaffected despite carrying this variant (PMID: 28588830). This variant is also known as IVS11+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 37566). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant results in increased abundance of the naturally occurring BRCA1 isoform lacking exon 10, and a shortened in-frame splice variant that removes a portion of this exon (PMID: 23239986). However, the shortened splice variants may retain some residual function (PMID: 8972225, 16943438, 11359908, 11431698), and therefore the clinical significance of this result is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Pathway Genomics RCV000031147 SCV000189880 likely pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031147 SCV000053747 likely pathogenic Breast-ovarian cancer, familial 1 2012-04-20 no assertion criteria provided clinical testing

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