ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.301+1G>A (rs587782173)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130778 SCV000185671 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing The c.301+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the BRCA1 gene. 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 the native splice donor site. Alterations at this donor site are known to produce an in frame transcript impacting four amino acids in the BRCA1 RING domain (Ambry internal data). One functional study found that nucleotide substitutions at this donor site are non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). However this alteration has also been identified in trans with a pathogenic mutation in BRCA1 in an individual without features of Fanconi Anemia (Ambry internal data, personal communication). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258401 SCV000325524 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000489155 SCV000577622 likely pathogenic not provided 2017-05-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.301+1G>A or IVS5+1G>A and consists of a G>A nucleotidesubstitution at the +1 position of intron 5 of the BRCA1 gene. This variant destroys a canonical splice donor site and ispredicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsensemediatedmRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published inthe literature. Based on the currently available information, we consider BRCA1 c.301+1G>A to be a likely pathogenicvariant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000506017 SCV000605736 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing The c.301+1G>A variant in BRCA1 has been reported in 1 Caucasian woman with brea st cancer who also carried another pathogenic variant in BRCA2 (Rebbeck 2016). T his variant has been identified in 1/111,504 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs5877821 73). This variant occurs in the invariant region (+/- 1,2) of the splice consens us sequence and variants in this region are predicted to cause altered splicing leading to an abnormal or absent protein. However, in vitro functional studies f or another variant at this exon-intron junction (301+6T>C) suggest the use of an alternative splice donor site resulting in an in-frame deletion of three amino acids (Thomassen 2012). Please note, these types of assays may not accurately re present biological function. In summary, due to conflicting and insufficient evi dence, the clinical significance of the c.301+1G>A variant is uncertain.
Invitae RCV000545203 SCV000635877 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the BRCA1 gene. This variant is present in population databases (rs587782173, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer (PMID: 27836010). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.301+1G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 142004). A experimental study has shown that a different variant (c.301+6T>C) results in an aberrant transcript encoding an in-frame deletion of 3 amino acids at the exon 5-6 junction (referred to as the exon 6-7 junction) (PMID: 21769658). While the effect of this variant (c.301+1G>A) has not been assessed experimentally, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant disrupts the consensus splice site. However, these algorithms also detect a cryptic donor splice site 9 nucleotides upstream, the use of which would lead to the in-frame deletion of 3 amino acids. These data suggest that an upstream, cryptic donor site can potentially rescue disruption of the canonical donor site, thereby preserving the integrity of the reading frame. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000489155 SCV000888880 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130778 SCV000912054 likely benign Hereditary cancer-predisposing syndrome 2017-09-12 criteria provided, single submitter clinical testing
Brotman Baty Institute,University of Washington RCV000258401 SCV001243801 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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