rs28897673
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BP6_Very_Strong
The NM_007294.4(BRCA1):c.314A>G(p.Tyr105Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,610,448 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 1 hom. )
Consequence
BRCA1
NM_007294.4 missense
NM_007294.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 1.32
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 -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.3143799).
BP6
Variant 17-43104249-T-C is Benign according to our data. Variant chr17-43104249-T-C is described in ClinVar as [Benign]. Clinvar id is 54780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104249-T-C is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.314A>G | p.Tyr105Cys | missense_variant | 6/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.314A>G | p.Tyr105Cys | missense_variant | 6/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes 0.0000788 AC: 12AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250980Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135634
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GnomAD4 exome AF: 0.000191 AC: 279AN: 1458246Hom.: 1 Cov.: 33 AF XY: 0.000179 AC XY: 130AN XY: 725684
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GnomAD4 genome 0.0000788 AC: 12AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74374
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ClinVar
Significance: Benign
Submissions summary: Benign:24
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:7
| Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| 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 = 0.000000105 - |
| Benign, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Likely benign, criteria provided, single submitter | literature only | Counsyl | Aug 19, 2014 | - - |
| Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
not specified Benign:6
| 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 | - | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2013 | 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 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | - - |
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | BRCA1: BP1, BS3:Supporting - |
Hereditary cancer-predisposing syndrome Benign:3
| 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2015 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 24, 2020 | - - |
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 | Oct 12, 2022 | - - |
Breast neoplasm Benign:1
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Inherited ovarian cancer (without breast cancer) Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Jun 26, 2024 | BS3_Strong,BP1,BP5_Very Strong - |
Hereditary breast ovarian cancer syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Endometrial carcinoma Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 p.Tyr105Cys variant was identified in 4 of 6744 proband chromosomes (frequency: 0.0006) from American, Spanish, Moroccan and Portuguese individuals or families with breast and breast/ovarian cancer (Borg_2010_20104584, Diez_2003_12955716, Laraqui_2013_23289006, Peixoto_2015_24916970). A hierarchcal statistical model of the data in the case control study (Borg_2010_20104584), found the variant to be neutral (Capanu_2011_21520273). A cDNA-based functional assay looking at the variant’s ability to functionally complement BRCA1-deficient mouse embryonic stem cells found the variant to be neutral, showing protein levels and cisplatin response comparable to wildtype (Bouwman_2013_23867111). In another functional assay looking at homology directed repair and single-strand annealing, the variant showed an intermediate phenotype, neither fully active nor fully defective, thereby classifying it as uncertain significance (Towler_2013_23161852). Using a method combining the bioinformatics tool A-GVGD, which assesses variation present at a missense position against multiple sequence alignments, and any co-occurrences with the variant, the variant was classified as uncertain significance (Tavtigian_2006_16014699). Two bioinformatics models that calculate posterior probability and likelihood ratio of pathogenicity, both integrating multiple forms of genetic evidence, found the variant to be not pathogenic or neutral (Lindor_2012_21990134, Easton_2007_17924331). The variant was also identified in dbSNP (ID: rs28897673) “With Likely benign allele”, ClinVar (benign, reviewed by an expert panel (2015); submitters: benign by ENIGMA, Michigan Medical Genetics Laboratories (University of Michigan), Ambry Genetics, Invitae, GeneDx, and BIC, and likely benign by Counsyl and CSER_CC_NCGL(University of Washington)), Clinvitae (5x), COGR (by 3 clinical labs classified as benign/likely benign and uncertain significance), LOVD 3.0, UMD-LSDB (22x as 1-neutral, co-occurring with a BRCA1 pathogenic variant (c.IVS6+1G>T/c.516+1G>T)), BIC Database (18x with no clinical importance, classification pending), ARUP Laboratories (not pathogenic, or of no clinical importance), and was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant also co-occurred in trans with known pathogenic BRCA1 variants (623del5 and 5385insC) (Judkins_2005_16267036). The variant was identified in control databases in 19 of 245822 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). Observation by population included: “Other” in 2 of 5482 chromosomes (freq: 0.0004), Latino in 3 of 33552 chromosomes (freq: 0.00009), European Non-Finnish in 14 of 111554 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Tyr105 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Cys variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;D;N;.;N;N;N;D;D;.
REVEL
Uncertain
Sift
Benign
T;D;D;T;D;T;D;T;D;D;D;.;D;D;D;T;D;.
Sift4G
Uncertain
D;T;T;D;T;T;.;.;D;.;D;.;D;.;D;.;.;.
Polyphen
0.43, 1.0, 1.0
.;B;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
Vest4
MVP
MPC
0.47
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at