rs80356892
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_007294.4(BRCA1):c.2566T>C(p.Tyr856His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,613,694 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y856C) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.2566T>C | p.Tyr856His | missense_variant | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2566T>C | p.Tyr856His | missense_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000604 AC: 92AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00167 AC: 419AN: 251004Hom.: 5 AF XY: 0.00142 AC XY: 192AN XY: 135680
GnomAD4 exome AF: 0.000458 AC: 669AN: 1461344Hom.: 5 Cov.: 41 AF XY: 0.000410 AC XY: 298AN XY: 726908
GnomAD4 genome ? AF: 0.000610 AC: 93AN: 152350Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52AN XY: 74504
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:7
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Jul 19, 2006 | - - |
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 = 0.00018. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01399 (Asian), derived from 1000 genomes (2012-04-30). - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Jul 04, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 25, 2011 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
not specified Benign:7
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 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, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 18, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
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 | GeneKor MSA | Nov 01, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 31, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 11, 2020 | - - |
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. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | BRCA1: BS1, BS2 - |
Familial cancer of breast Benign:2
Likely benign, no assertion criteria provided | curation | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Hereditary breast ovarian cancer syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 03, 2016 | - - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 21, 2022 | - - |
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 BRCA1 p.Tyr856His variant was identified in 21 of 4034 proband chromosomes (frequency: 0.0.005) from Korean, Malaysian and Japanese individuals or families with breast cancer, and was not identified in 718 control chromosomes from healthy individuals (Han S-H 2006, Thirthagiri 2008, Toh 2008, Mitsuru Emi 1998). The variant was (also) identified by our laboratory in 6 individuals with breast or ovarian cancer, with one individual in the presence of a second BRCA1 pathogenic variant (c.81-?_134+?del). In a functional complementation assay using BRCA1-deficient mouse embryonic stem cells, the variant was found to be neutral (Bouwman 2013). Promkan et al (2013), showed that BRCA1 (Tyr856His)-transfected mutant cells interfered with the function of wildtype BRCA1 by increased cellular proliferation, which may have implications for chemotherapeutic treatment. Multiple in silico prediction and evolutionary models show that the variant is neutral (Abkevich 2004, Burk-Herrick 2005, Lindor 2012, Spearman 2008, Tavtigian 2006) The variant was identified in dbSNP (ID: rs80356892) “With Likely benign allele”, Clinvitae database (classification benign/likely benign), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database (classification not pathogenic), the ClinVar database (classification benign, reviewed by an expert panel, submitters: ENIGMA, Ambry Genetics, Counsyl, Invitae, Gene Dx, Sharing Clinical Report Project (SCRP) (derived from Myriad reports), classification likely benign by CSER, and uncertain significance by BIC), GeneInsight COGR database (unclassified, “by a clinical laboratory(ies)”), the BIC database (18X with unknown clinical importance, pending classification), and UMD (6X with a “neutral” classification). The variant was also identified in 1000 Genomes Project in 15 of 5000 chromosomes (frequency: 0.003), HAPMAP-EAS in 14 of 1008 chromosomes (frequency: 0.0139), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), NHLBI GO Exome Sequencing Project (ESP) in 1 of 4406 African American alleles (frequency: 0.0002), and the the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 184 of 121322 chromosomes (frequency: 0.0015) (or 180 individuals (3 homozygous) from a population of East Asian individuals, 3 South Asian and 1 Latino individual. In addition, this variant is classified as a polymorphism by Myriad (personal communication). The p.Tyr856 residue is not conserved in mammals and lower organisms, and the variant amino acid His is present in African clawed frog, increasing the likelihood that this variant does not have clinical significance. Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at