17-43067608-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_007294.4(BRCA1):c.5074G>C(p.Asp1692His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000275 in 1,454,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1692N) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 missense, splice_region
NM_007294.4 missense, splice_region
Scores
11
6
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.72
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43067608-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.818
PP5
Variant 17-43067608-C-G is Pathogenic according to our data. Variant chr17-43067608-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 37633.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067608-C-G is described in Lovd as [Pathogenic]. Variant chr17-43067608-C-G is described in Lovd as [Likely_pathogenic]. Variant chr17-43067608-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.5074G>C | p.Asp1692His | missense_variant, splice_region_variant | 16/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.5074G>C | p.Asp1692His | missense_variant, splice_region_variant | 16/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251348Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
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GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454204Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 723848
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30
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1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 23, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 17, 2010 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This missense variant replaces aspartic acid with histidine at codon 1692 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). RNA studies reported that this variant causes aberrant mRNA splicing that introduces either a frameshift and/or a premature termination codon in patient RNA and minigene splicing assay (PMID: 21769658, 22505045, 25724305). Functional studies also have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation and haploid cell proliferation assays (PMID: 20516115, 30209399, 32546644). This variant has been reported in at least six individuals affected with breast and/or ovarian cancer (PMID: 21769658, 23239986, 28294317, https://doi.org/10.1515/tjb-2019-0424). This variant has also been identified in 3/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In addition, different variants affecting the same position (c.5074G>A, c.5074G>T) are considered to be disease-causing (ClinVar variation ID: 37632, 55376), suggesting that the nucleotide at this position is important for normal RNA splicing. Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Nov 25, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anaemia, complementation group S (MIM#617883), susceptibility to breast and ovarian cancer (MIM#604370) and susceptibility to pancreatic cancer (MIM#614320). (I) 0108 - This gene is associated with both recessive and dominant disease. Susceptibility to breast and ovarian cancer follows an autosomal dominant inheritance pattern, while Fanconi anaemia is inherited in an autosomal recessive pattern (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. The highest estimate for cancer risk in carriers of pathogenic variants is 80% by the age of 70 years (PMID: 30551077). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in the BRCA1 C terminus domain in a cluster of pathogenic missense variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ENIGMA expert panel and has been reported as pathogenic by numerous other clinical laboratories (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 29, 2023 | The BRCA1 c.5074G>C (p.Asp1692His) variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 22762150 (2012), 21769658 (2012), 23239986 (2012), 30702160 (2019), and 33629534 (2021)). It has also been reported in an individual with bladder cancer (PMID: 31794323 (2020)). Functional studies have shown that this variant is damaging to protein function and aberrant splicing can result in exon 17 skipping (PMIDs: 25724305 (2015) and 30209399 (2018)). However, the loss of exon 17 has also been observed in naturally occurring BRCA1 isoforms (PMID: 23239986 (2012)). Additional functional studies have reported conflicting results on the effect of this variant on BRCA1 protein function (PMID: 20516115 (2010)). The frequency of this variant in the general population, 0.000012 (3/251348 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2023 | Published functional studies demonstrate a damaging effect: impaired transcriptional activity and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (PMID: 20516115, 28781887, 30209399, 30765603, 33087888); Multifactorial likelihood analysis suggests this variant is pathogenic (PMID: 31131967); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5193G>C; This variant is associated with the following publications: (PMID: 22762150, 21769658, 29053726, 33629534, 31131967, 20516115, 14647443, 22505045, 25782689, 23239986, 25724305, 28781887, 30209399, 30765603, 33087888, 30787465, 25348405, 31447099, 30702160, 29446198, 29922827, 31794323, 31825140) - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2017 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 12, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 11, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in two alternately spliced products, one with skipping of exon 16 and another with retention of 153 nucleotides of intron 16 and introduces a premature termination codon (PMID: 20516115, 21769658, 22505045, 23239986, 25724305, 30209399; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 37633). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 21769658, 22505045, 22762150, 23239986, 28294317, 29446198, 30702160). This variant is present in population databases (rs80187739, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1692 of the BRCA1 protein (p.Asp1692His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2023 | 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 alteration 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 variant 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 (Ambry internal data; 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). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature 2018 Oct;562(7726):217-222). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 11, 2022 | This missense variant replaces aspartic acid with histidine at codon 1692 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). RNA studies reported that this variant causes aberrant mRNA splicing that introduces either a frameshift and/or a premature termination codon in patient RNA and minigene splicing assay (PMID: 21769658, 22505045, 25724305). Functional studies also have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation and haploid cell proliferation assays (PMID: 20516115, 30209399, 32546644). This variant has been reported in at least six individuals affected with breast and/or ovarian cancer (PMID: 21769658, 23239986, 28294317, https://doi.org/10.1515/tjb-2019-0424). This variant has also been identified in 3/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In addition, different variants affecting the same position (c.5074G>A, c.5074G>T) are considered to be disease-causing (ClinVar variation ID: 37632, 55376), suggesting that the nucleotide at this position is important for normal RNA splicing. Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Ovarian neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T;.;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;M;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;N;.;D;.;N;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D;.;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;.;.;D
Polyphen
0.99, 1.0
.;D;.;.;.;.;.;.;D;.
Vest4
MVP
MPC
0.25
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at