ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5074G>C (p.Asp1692His) (rs80187739)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220578 SCV000277819 pathogenic Hereditary cancer-predisposing syndrome 2017-12-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Breast Cancer Information Core (BIC) (BRCA1) RCV000031214 SCV000145294 pathogenic Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031214 SCV000326136 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031214 SCV000785478 pathogenic Breast-ovarian cancer, familial 1 2017-08-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048768 SCV000591568 pathogenic Hereditary breast and ovarian cancer syndrome 2013-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000256114 SCV000322068 likely pathogenic not provided 2016-10-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5074G>C at the cDNA level. Using alternate nomenclature, this variant has been previously published as BRCA1 5193G>C. Although the nucleotide substitution results in the change of an Aspartic Acid to a Histidine at codon 1692, and is called Asp1692His in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing. BRCA1 c.5074G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The nucleotide which is altered, a guanine (G) at base 5074, is conserved through mammals.Multiple splicing models predict that this variant may greatly weaken or destroy the natural splice donor site and lead to abnormal splicing. In vitro studies demonstrate that this exonic splicing variant leads to multiple aberrant transcripts. One such alternate transcript demonstrates skipping of exon 17; however naturally occurring BRCA1 isoforms exist where exon 17 is skipped (Wappenschmidt 2012, Ahlborn 2015). Importantly, a second aberrant transcript has been observed in which a cryptic splice site is activated leading to retention of 153 nucleotides of intron 17 within the spliced transcript (Wappenschmidt 2012, Thomassen 2012, Ahlborn 2015). Thus, significant in vitro evidence suggests pathogenicity, although given the alternate splicing mechanism of the variant, the in vivo effect is less clear. Based on the currently available information, we consider BRCA1 c.5074G>C to be a likely pathogenic variant.
GeneKor MSA RCV000256114 SCV000693542 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785420 SCV000923992 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000048768 SCV000699198 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5074G>C (p.Asp1692His) variant involves the alteration of a conserved nucleotide at the exon 17-intron 17 junction and results in a missense subtitution. 5/5 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts that this variant may affect several ESE sites at the locus. Functional studies have demonstrated in vitro splicing aberrations caused by the variant, including exon 17 skipping (Wappenschmidt_PLos One_2012; Ahlborn_BCRT_2015) and retention of 153bp of intron 17 that is predicted to result in a truncated protein (Ahlborn_BCRT_2015; Wappenschmidt_PLos One_2012; Thomassen_BRCA1&2_BCRT_2011). One study also showed a significant or total reduction of WT transcript via RT-PCR and agarose gel band sequence analysis (Thomassent_BRCA1&2_BCRT_2011). The variant lies within the BRCT domain and a functional study showed that a cell line with the variant had a 31% reduction in DNA repair (Coupier_Oncogene_2004). This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/121082 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000048768 SCV000076781 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 1692 of the BRCA1 protein (p.Asp1692His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. It also falls at the last nucleotide of exon 16 of the BRCA1 coding sequence. This variant is present in population databases (rs80187739, ExAC 0.002%). This variant has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 21769658, 22762150, 22505045, 23239986, 28294317). ClinVar contains an entry for this variant (Variation ID: 37633). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change disrupts normal splicing and leads to two alternately spliced products; one with skipping of exon 16 and another with retention of 153 base pairs of intron 16. This is expected to result in an absent or disrupted protein product and compromized transcription activation activity. (PMID: 21769658, 22505045, 23239986, 25724305, 20516115). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048768 SCV000966915 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-27 criteria provided, single submitter clinical testing The p.Asp1692His variant in BRCA1 has been reported in at least 7 individuals wi th BRCA1-associated cancers (Lecarpentier 2012, Houdayer 2012, Thomassen 2012, W appenschmidt 2012, Breast Cancer Information Core (BIC) database: https://resear ch.nhgri.nih.gov/bic/) and has also been reported by other clinical laboratories in ClinVar (Variation ID: 37633). This variant has been identified in 1/9848 As hkenazi Jewish chromosomes, 1/111614 European chromosomes and 1/33580 Latino chr omosomes (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs80187739). This fre quency is low enough to be consistent with the frequency of hereditary breast an d ovarian cancer (HBOC) in the general population. This variant is located in th e last three bases of the exon, which is part of the 5? splice region. Multiple functional studies using patient RNA provide some evidence that the p.Asp1692His variant causes aberrant splicing (Houdayer 2012, Thomassen 2012, Wappenschmidt 2012, Ahlborn 2015, Woods 2016). In addition, computational prediction tools an d conservation analysis suggest that the p.Asp1692His variant may impact the pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.Ala1623Gly variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PS4_Moderate; PS3_Moderate.
Sharing Clinical Reports Project (SCRP) RCV000031214 SCV000053814 pathogenic Breast-ovarian cancer, familial 1 2010-11-17 no assertion criteria provided clinical testing

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