ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5074G>C (p.Asp1692His) (rs80187739)

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Total submissions: 17
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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) RCV000031214 SCV001161554 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.996159
Invitae RCV000048768 SCV000076781 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-02 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 observed in several individuals with a personal and/or family history of breast and ovarian cancer (PMID: 21769658, 22762150, 22505045, 23239986, 28294317, 29446198, 30702160). 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 nucleotides of intron 16. This is expected to result in an absent or disrupted protein product and compromised transcription activation activity (PMID: 21769658, 22505045, 23239986, 25724305, 20516115, 30209399). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000220578 SCV000277819 pathogenic Hereditary cancer-predisposing syndrome 2017-12-26 criteria provided, single submitter clinical testing The c.5074G>C pathogenic mutation (also known as p.D1692H), located in coding exon 15 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5074. The amino acid change results in aspartic acid to histidine at codon 1692, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in multiple families affected with phenotypes consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Lecarpentier J et al. Breast Cancer Res. 2012 Jul 3;14(4):R99; Thomassen M et al. Breast Cancer Res Treat. 2012 Apr;132(3):1009-23). This mutation has also been shown by functional splicing assays to result in abnormal protein transcripts by either skipping of coding exon 15 or in-frame retention of a portion of intron 15 (Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38; Wappenschmidt B et al. PLoS One. 2012;7(12):e50800; Ahlborn LB et al. Breast Cancer Res. Treat., 2015 Apr;150:289-98). Note that this alteration is also referred to as 5193G>C in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
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.
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
GeneKor MSA RCV000256114 SCV000693542 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant is a single amino acid change from Aspartic acid to Histidine at amino acid residue 1692 of the BRCA1 gene. The Aspartic acid residue is highly conserved among species and it is located in a functional domain of the protein. There is a moderate physiochemical difference between Aspartic acid and Histidine (Grantham Score 81). This variant is present in population databases at a very low frequency (rs80187739, ExAC 0.002%) and it has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 21769658, 22762150, 22505045). This variant occurs at the last nucleotide of exon 16 of the BRCA1 coding sequence which is highly conserved in the human and other genomes, and is part of the consensus splice site. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681). Experimental studies have shown that this missense change disrupts normal splicing and leads to two alternately spliced products; one lucking 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 compromised transcription activation activity (PMID: 21769658, 22505045, 25724305). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. The mutation database ClinVar contains entries for this variant (Variation ID: 37633).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Counsyl RCV000031214 SCV000785478 pathogenic Breast-ovarian cancer, familial 1 2017-08-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000048768 SCV000966915 likely pathogenic Hereditary breast and ovarian cancer syndrome 2021-01-12 criteria provided, single submitter clinical testing The p.Asp1692His variant in BRCA1 has been reported in at least 7 individuals with BRCA1-associated cancers (Lecarpentier 2012 PMID: 22762150, Houdayer 2012 PMID: 22505045, Thomassen 2012 PMID: 21769658, Wappenschmidt 2012 PMID: 23239986, Rebbeck 2018 PMID: 29446198, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 1/10078 Ashkenazi Jewish chromosomes, 1/113660 European chromosomes and 1/34586 Latino chromosomes in gnomAD (http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is located in the 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 PMID: 22505045, Thomassen 2012 PMID: 21769658, Wappenschmidt 2012 PMID: 23239986, Ahlborn 2015 PMID: 25724305, Woods 2016 PMID: 28781887). In addition, computational prediction tools and conservation analysis suggest that the p.Asp1692His variant may impact the protein. Moreover, this variant was classified as pathogenic on June 18th 2019, by the ClinGen-approved ENIGMA expert panel (Variation ID 37633). In summary, although additional studies are required to fully establish its clinical significance, the p.Ala1623Gly variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate; PM2_Supporting; PS3_Moderate, PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256114 SCV001133606 likely pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient in literature. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color Health, Inc RCV000220578 SCV001346671 pathogenic Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659880 SCV001877436 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) RCV000031214 SCV000053814 pathogenic Breast-ovarian cancer, familial 1 2010-11-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031214 SCV000145294 pathogenic Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353883 SCV000591568 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Asp1692His variant was identified by Coupier (2004) in an individual with breast cancer, and was also identified in the following databases: dbSNP (ID: rs80187739) “With pathogenic, probable-pathogenic, untested allele”, HGMD, UMD (2X as a causal variant), BIC (3X with clinical importance) and LOVD. The p.Asp1692 residue is conserved in mammals and lower organisms and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Asp1692His variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The c.5074G>C mutation occurs at the last base of the exon, a position which has been shown to be part of the splicing consensus sequence, and variants involving this position sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 4 of 4 different programs, supporting a pathogenic role for this variant. There are conflicting results in the literature regarding the effect of the variant on splicing and protein function. Two studies detected a cryptic splice site in intron 17 by RT-PCR, with a predicted frame-shift and truncation of the encoded protein (Thomassen 2012, Wappenschmidt 2012). In addition, Wappenschmidt (2012) found that the variant enhanced exon 17 skipping compared to controls; this effect was also reported by Houdayer (2012), though it should be noted that transcripts lacking exon 17 have been found in controls, representing a naturally occurring isoform (Wappenschmidt 2012). Another study did not detect any abnormal transcript from a proband with this variant (Coupier 2004). Assays evaluating peptide binding and structural stability (Lee 2010), or DNA repair (Coupier 2004) yielded intermediate or inconclusive results as compared to wild-type protein function. In summary, based on the above information and the consensus from several of the above sources supports a more pathogenic role for this variant. This variant is classified pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785420 SCV000923992 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000031214 SCV001237531 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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