ClinVar Miner

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

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Total submissions: 15
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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) 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G variant may not exhibit the clinical characteristics of a standard high-risk pathogenic BRCA1 variant (Spurdle, unpublished data).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.
Invitae RCV000048442 SCV000076455 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-22 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, 31683985), and was observed to segregate with disease (PMID: 31683985, Invitae). However, it has also been observed as homozygous in two individuals: a healthy 58-year-old woman from a consanguineous family, whose 87-year-old mother was unaffected despite carrying this variant (PMID: 28588830), and a woman with lung cancer and cafe-au-lait spots (PMID: 31683985). 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.
Ambry Genetics RCV000164655 SCV000215320 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing The c.4096+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 9 in the BRCA1 gene. Studies from carrier blood lymphocytes have demonstrated that this alteration results in aberrant splicing leading to an increase in the amount of transcript lacking all of exon 9 (also known as <span style="font-family:dejavusans">&Delta;11) and another lacking most of the 3' end of exon 9 (also known as <span style="font-family:dejavusans">&Delta;11q and <span style="font-family:dejavusans">&Delta;11b) (Wappenschmidt B et al. PLoS ONE. 2012;7:e50800; Ambry internal data). Both of these alterations are in-frame losses and both have been reported as naturally occurring isoforms in blood and other tissues, including mammary gland (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Thakur S et al. Mol. Cell. Biol. 1997 Jan;17:444-52; Magdinier F et al. Oncogene. 1999 Jul;18:4039-43; Wilson CA et al. Oncogene. 1997 Jan;14:1-16). Functional studies have shown that the protein generated by the isoform lacking exon 9 is unable to form Rad51 foci and that the protein generated by both isoforms may also be mislocalized to the cytoplasm; however, not all studies agree on the latter point (Huber LJ et al. Mol. Cell. Biol. 2001 Jun;21:4005-15; Thakur S et al. Mol. Cell. Biol. 1997 Jan;17:444-52; Wilson CA et al. Oncogene. 1997 Jan;14:1-16). A homozygous knock-in mouse model of the isoform lacking exon 9 did not result in overt developmental defects; however, there were mammary gland abnormalities and spontaneous tumor formation (Kim SS et al. Mol. Cell. Biol. 2006 Sep;26:6983-92). This alteration has been reported in multiple cohorts of breast and ovarian cancer (Beissel JM et al. Gynecol Oncol Rep. 2014 Dec;10:25-7; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Machackova E et al. Klin Onkol. 2019;32:51-71; Arason A et al. Genes (Basel). 2019 11;10:); however, it was also identified in a homozygous state in an individual who was ascertained for but did not have Fanconi Anemia (Byrjalsen A et al. Clin Case Rep. 2017 Jun;5:876-879). Of note, this alteration is also referred to as IVS11+3A>G in published literature. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish and weaken the native splice donor site, respectively. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
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
GeneDx RCV000481455 SCV000568407 uncertain significance not provided 2019-05-20 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate 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); Observed in individuals with breast and/or ovarian cancer (Borg 2010, Beissel 2014, Song 2014); Also known as BRCA1 4215+3A>G, IVS11+3A>G, and 4216nt-2A>G; This variant is associated with the following publications: (PMID: 28195393, 11431698, 28588830, 8972225, 16943438, 11359908, 20104584, 17591843, 24728189, 19383375, 26075997, 23239986, 31683985)
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
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 (https://enigmaconsortium.org/wp-content/uploads/2017/12/ENIGMA_Rules_2017-06-29.pdf). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779901 SCV000916803 uncertain significance not specified 2019-08-09 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 that 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 5' 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 254008 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. c.4096+3A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Borg_2010, Wappenschmidt_2012, Song_2014, 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). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) with conflicting interpretations (uncertain significance X6; pathogenic/ likely pathogenic X2). Based on the evidence outlined above, the variant was classified as uncertain significance until additional functional or segregation data becomes available.
Color Health, Inc RCV000164655 SCV001359352 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-06 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the +3 position of intron 10 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Functional study showed splicing defects leading to reduced wild-type transcript and two alternative transcript predicted to cause in-frame deletion, including the naturally occurring skipping of exon 10 (PMID 23239986). This variant has been reported in individuals affected with breast and ovarian cancer (PMID 23239986, 28588830) and colorectal cancer (PMID 28195393). However, segregation data from one consanguineous family suggests the variant does not show strong co-segregation with disease or has low penetrance (PMID 28588830). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Research and Development, ARUP Laboratories RCV001659840 SCV001877381 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031147 SCV000053747 likely pathogenic Breast-ovarian cancer, familial 1 2012-04-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031147 SCV000144972 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Pathway Genomics RCV000031147 SCV000189880 likely pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481455 SCV000591489 uncertain significance not provided no assertion criteria provided clinical testing The BRCA1 c.4096+3A>G variant was identified in 3 of 8746 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer (Borg 2010, Wappenschmidt 2012, Song 2014). The variant was identified in dbSNP (rs80358015) as “with likely pathogenic allele”, ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, Integrated Genetics and 4 other submitters, pathogenic by Lady Davis and 1 other submitter, likely pathogenic by Pathway Genomics and SCRP and likely benign by Institute of Cancer Research ), LOVD 3.0 (observed 4x) and UMD-LSDB (observed 1x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (March 6, 2019, v2.1.1). The variant was identified in our laboratory in a breast cancer family in 1 affected and 3 unaffected individuals. In addition, the variant was identified in a consanguineous family in an unaffected homozygous carrier, suggesting it may not have a clinical effect (Byrjalsen 2017). The variant causes a partial deletion of exon 10, but doesn’t fully abolish transcript production (Wappenschmidt 2012, Kim 2006, Huber 2001, Thakur 1997). The c.4096+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 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.
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

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