17-43093883-T-G
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_007294.4(BRCA1):c.1648A>C(p.Asn550His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,613,938 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00035 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 7 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 0.0880
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 Benign. Variant got -18 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.103633314).
BP6
Variant 17-43093883-T-G is Benign according to our data. Variant chr17-43093883-T-G is described in ClinVar as [Benign]. Clinvar id is 37423.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093883-T-G is described in Lovd as [Benign]. Variant chr17-43093883-T-G is described in Lovd as [Likely_benign]. Variant chr17-43093883-T-G is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000335 (489/1461604) while in subpopulation MID AF= 0.0179 (103/5746). AF 95% confidence interval is 0.0151. There are 7 homozygotes in gnomad4_exome. There are 256 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 7 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.1648A>C | p.Asn550His | missense_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.1648A>C | p.Asn550His | missense_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes 0.000348 AC: 53AN: 152216Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000259 AC: 65AN: 250836Hom.: 0 AF XY: 0.000339 AC XY: 46AN XY: 135600
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GnomAD4 exome AF: 0.000335 AC: 489AN: 1461604Hom.: 7 Cov.: 34 AF XY: 0.000352 AC XY: 256AN XY: 727098
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GnomAD4 genome 0.000348 AC: 53AN: 152334Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74488
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ClinVar
Significance: Benign
Submissions summary: Uncertain:3Benign:35
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:10
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 19, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, flagged submission | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, criteria provided, single submitter | literature only | Counsyl | Apr 07, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
| Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000000000163 - |
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 01, 2015 | - - |
| Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
not specified Uncertain:1Benign:9
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 28, 2020 | Variant summary: BRCA1 c.1648A>C (p.Asn550His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 282970 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00026 vs 0.001), allowing no conclusion about variant significance. c.1648A>C has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Adem_2002, Guidugli_2011, Jalkh_2005, Augello_2006, Spurdle_2008, Solano_2013, Mahfoudh_2012, Wong-Brown_2015, Biunno_2014, Maresca_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in our lab and other databases (BRCA1 c.5080G>T, p.Glu1694X; BRCA2 c.6082_6086delGAAGA, p.Glu2028LysfsX19; BRCA1 c.962G>A, p.Trp321Ter ; BRCA1 c.3544C>T, p.Gln1182Ter ; BRCA2 c.5682C>G, p.Tyr1894Ter ; BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. At least two publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Guidugli_2011, Maresca_2018). 13 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x), likely benign (7x) and benign (3x), including one expert panel (ENIGMA, benign). Based on the evidence outlined above, the variant was classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 19, 2022 | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 04, 2015 | - - |
| Uncertain significance, flagged submission | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 7 B/LB, including expert panel - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
not provided Benign:6
| Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 02, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 01, 2022 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 18, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 16, 2017 | - - |
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | BRCA1: BP1, BS3:Moderate, BS1 - |
Hereditary cancer-predisposing syndrome Benign:4
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 25, 2020 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 05, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 15, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Uncertain significance, flagged submission | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 02, 2015 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 07, 2022 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 22, 2023 | - - |
BRCA1-related cancer predisposition Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | - - |
Breast neoplasm Benign:1
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Malignant tumor of breast Benign:1
| Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Asn550His variant has been identified in 8 of 1464 proband chromosomes (frequency 0.005) in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, El-Harith 2002 12070551, Jalkh 2012, Russo 2007, Solano 2012) and was absent in 200 control chromosomes from these studies. Myriad reports this variant as a polymorphism, and the Exome Server Project reports a frequency of 0.0003 in European American alleles, and 0.0002 in African American alleles. This variant has been also been reported in dbSNP (ID: rs56012641) “with non-pathogenic allele”, in the BIC database 54X as a variant of unknown clinical importance, and in UMD 19X as a neutral variant which co-occurred with a known pathogenic mutation, BRCA2 c.6082 6086delGAAGA (p.Glu2028LysfsX19), increasing the likelihood that the p.Asn550His variant does not have clinical significance. The p.Asn550 residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. Functional assays on the p. Asn550His variant have suggested that it has a neutral effect on BRCA1 function in homologous repair (Caligo 2008) and non-homologous end-joining (Guidugli 2011). Many studies have identified the p.Asn550His variant co-occurring with two other BRCA1 variants, p.Tyr179Cys and p.Phe486Lys, in individuals with breast or ovarian cancers (Augello 2006, Caligo 2008, Diez 2003, Jalkh 2012), suggesting that together they constitute a rare haplotype (Tavtigian 2006). Furthermore, Augello (2006) identified these three mutations in three members of one family indicating that they exist in cis, and suggests that the presence of the three variants might produce an effect on the conformation of the protein and, consequently, on its function. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;.;D;D
Sift4G
Uncertain
D;D;D;D;.;D;.
Polyphen
D;.;.;P;.;.;.
Vest4
MVP
MPC
0.44
ClinPred
T
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at