ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5332G>A (p.Asp1778Asn) (rs80357112)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131398 SCV000186374 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,RNA Studies,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Breast Cancer Information Core (BIC) (BRCA1) RCV000077615 SCV000145462 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077615 SCV000326273 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000587684 SCV000293459 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5332G>A at the cDNA level, p.Asp1778Asn (D1778N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). Using alternate nomenclature, this variant would be defined as BRCA1 5451G>A. Splicing assays suggest that this variant results in skipping of exon 20, reported as exon 21 in the literature due to alternate exon numbering, leading to a frameshift (Houdayer 2012, Ahlborn 2015). However, alternative splicing resulting in skipping of exon 20, reported as exon 21, has also been identified in blood and breast tissues from healthy controls (Colombo 2014). In addition, this variant has been reported in trans with a pathogenic BRCA1 variant in one individual and in cis with a different BRCA1 pathogenic variant in another, suggesting it is not disease-causing (Tischkowitz 2008, Cherbal 2012). Studies analyzing protein function have demonstrated BRCA1 Asp1778Asn to exhibit mildly decreased cell survival, Rad51 foci formation, and protein stabilization, but normal homology-directed repair, protein folding, binding activity and specificity, and transcription (Rowling 2010, Lee 2010, Gaboriau 2015). Of note, these assays measure the impact of the resulting missense change as opposed to a splicing defect. BRCA1 Asp1778Asn was not observed in large population cohorts (Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Asp1778Asn occurs at a position that is conserved in mammals and is located in the second BRCT domain and a region known to interact with multiple proteins (Paul 2014, UniProt). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, it is unclear whether BRCA1 Asp1778Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587684 SCV000699239 uncertain significance not provided 2016-09-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5332G>A (p.Asp1778Asn) variant, alternatively also known as 5451G>A and IVS 21 G-A -1, involves the alteration of the conserved nucleotide at exon-intron boundary. 2/4 in silico tools predict a damaging outcome for this variant. This variant is absent in approximately 120686 control chromosomes from ExAC. This variant has been reported in multiple affected individuals affected with HBOC in literature and clinical databases. However, in two cases (Cherbal_2012 and Tischkowitz_2008), the variant co-occurred with another pathogenic BRCA1 variant, c.798_799delTT (p.Ser267LysfsX19) and c.5324T>G (p.M1775K); both classified as pathogenic by our lab and other labs in ClinVar. 4/5 in silico programs predict the variant to affect normal splicing, which was also confirmed by functional studies (Houdayer_2012 and Ahlborn_2015). But additional functional studies (Lee_2010 and Rowling_2010) also showed that the variant protein acted similar to wild-type in terms of folding, peptide binding activity and specificity and transcriptional activity (Lee_2010, Rowling_2010). Furthermore, the quantification of cells performing homologous recombination after transfection with BRCA1 and mutants showed that variant had comparable functional activity with that of wildtype (Gaboriau_2015). Multiple publications using various algorithms provide conflicting interpretations of the variant being benign or pathogenic. Multiple clinical labs via ClinVar list the variant with a classification of VUS, without evidence to independently evaluate. Taken all evidence into consideration, this variant is currently classified as a variant of unknown significance (VUS).
Invitae RCV000048936 SCV000076949 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1778 of the BRCA1 protein (p.Asp1778Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant also falls at the last nucleotide of exon 20 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 22684231, 18285836, 28364669). Although it has been reported to co-occur in trans with a pathogenic BRCA1 variant, which suggests this may be a neutral variant, the parental genotyping data supporting this observation was not provided. Therefore, it cannot be verified unambiguously as occurring in trans (PMID: 22684231). ClinVar contains an entry for this variant (Variation ID: 55530). Transcriptional studies, which include both a minigene assay and an RT-PCR analysis using mRNA isolated from patient lymphocytes, show that this variant results in exon 21 skipping (PMID: 25724305, 22505045). Skipping of exon 21 is expected to result in an out-of-frame, non-functional BRCA1 protein. Experimental studies have also shown that this missense change does not affect BRCA1 protein function (PMID: 20516115, 20378548, 25748678). In summary, this is a rare variant that is reported to result in altered mRNA that lacks exon 21. It has also been reported to co-occur in trans with a pathogenic BRCA1 variant. However, because this latter observation could not be verified, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000077615 SCV000109418 uncertain significance Breast-ovarian cancer, familial 1 2010-10-22 no assertion criteria provided clinical testing

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