ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5406+5G>T (rs80358073)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562618 SCV000661028 likely pathogenic Hereditary cancer-predisposing syndrome 2016-11-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000031248 SCV000145493 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
GeneDx RCV000160008 SCV000210219 likely pathogenic not provided 2016-04-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 IVS21+5G>T or c.5406+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 21 of the BRCA1 gene. Multiple in silico models predict this variant to result in either a decrease or complete loss of the natural splice donor site, likely leading to abnormal gene splicing. This variant, also known as IVS22+5G>T or c.5525+5G>T using alternate nomenclature, has been reported in at least one woman with a history of breast cancer (Olopade 2003). While functional studies have not been performed on this variant, an RT-PCR study of a different variant at the same nucleotide position, BRCA1 c.5406+5G>A, demonstrated exon skipping leading a frameshift and premature termination (Petrij-Bosch 1997). BRCA1 c.5406+5G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. We consider this variant to be likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000780995 SCV000918739 uncertain significance not specified 2018-05-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5406+5G>T 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: two predict the variant abolishes a 5 splicing donor site and three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. At least one study has shown that one different variant affecting this nucleotide (c.5406+5G>C) affects mRNA splicing, resulting in skipping of exon 22 (Houdayer_2012) and has been observed in individuals and families affected with breast and/or ovarian cancer (PMID: 24010542, 26083025, 14985394, 9354803, 10090482) supporting the conserved nature of this nucleotide position. The variant was absent in 277096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5406+5G>T, has been reported in the literature in one affected individual with a clinical history of breast cancer (Susswein_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact of this specific variant on protein function and/or alternate splicing has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (2x) and VUS (1x). Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence pertaining to its co-segregation with breast/ovarian cancer in multiple independent individuals/families and a proven effect on nucleotide specific alternative splicing is obtained.
Invitae RCV000476190 SCV000549369 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-11-21 criteria provided, single submitter clinical testing This sequence change falls in intron 21 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 (rs80358073, ExAC no frequency). This variant has been reported in individuasl affected with breast cancer (PMID: 12491487, 26681312), although no segregation data was reported. This variant is also known as IVS22+5G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37667). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that two different variants affecting this nucleotide (c.5406+5G>A and c.5406+5G>C) affect mRNA splicing, resulting in skipping of exon 22 of the BRCA1 mRNA (PMID: 9354803, 22505045). In addition, these variants have been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 24010542, 26083025, 14985394, 9354803, 10090482), indicating that this nucleotide may be crucial for normal RNA splicing. 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.
Sharing Clinical Reports Project (SCRP) RCV000031248 SCV000053852 pathogenic Breast-ovarian cancer, familial 1 2011-06-20 no assertion criteria provided clinical testing

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