17-43092965-A-G

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 (★★★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00046 ( 5 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

2
11
5

Clinical Significance

Benign reviewed by expert panel U:1B:31

Conservation

PhyloP100: 3.23
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013050497).
BP6
Variant 17-43092965-A-G is Benign according to our data. Variant chr17-43092965-A-G is described in ClinVar as [Benign]. Clinvar id is 54604.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092965-A-G is described in Lovd as [Benign]. Variant chr17-43092965-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00061 (93/152350) while in subpopulation EAS AF= 0.017 (88/5190). AF 95% confidence interval is 0.0141. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA1NM_007294.4 linkc.2566T>C p.Tyr856His missense_variant Exon 10 of 23 ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.2566T>C p.Tyr856His missense_variant Exon 10 of 23 1 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
AF:
0.000604
AC:
92
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0167
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.00167
AC:
419
AN:
251004
Hom.:
5
AF XY:
0.00142
AC XY:
192
AN XY:
135680
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0219
Gnomad SAS exome
AF:
0.000262
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000655
GnomAD4 exome
AF:
0.000458
AC:
669
AN:
1461344
Hom.:
5
Cov.:
41
AF XY:
0.000410
AC XY:
298
AN XY:
726908
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0138
Gnomad4 SAS exome
AF:
0.000441
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.00118
GnomAD4 genome
AF:
0.000610
AC:
93
AN:
152350
Hom.:
0
Cov.:
32
AF XY:
0.000698
AC XY:
52
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0170
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000402
Hom.:
0
Bravo
AF:
0.000718
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00152
AC:
184
Asia WGS
AF:
0.00606
AC:
21
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:31
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:7
Jul 19, 2006
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 21, 2016
Michigan Medical Genetics Laboratories, University of Michigan
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 10, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

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). -

Feb 25, 2011
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 04, 2014
Counsyl
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:7
Apr 18, 2017
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 10, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 01, 2017
GeneKor MSA
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Jul 12, 2017
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 31, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 11, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

not provided Benign:3
Apr 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRCA1: BS1, BS2 -

Sep 04, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Familial cancer of breast Benign:2
-
Center for Precision Medicine, Meizhou People's Hospital
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: curation

- -

Feb 23, 2017
Baylor Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 16, 2021
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Mar 03, 2016
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S Benign:1
Feb 19, 2016
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Benign:1
Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
May 21, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast neoplasm Benign:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Malignant tumor of breast Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.059
T
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;.;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.82
T;T;T;T
MetaRNN
Benign
0.013
T;T;T;T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Uncertain
2.5
M;M;.;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.7
D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.015
D;D;D;D
Sift4G
Uncertain
0.035
D;D;D;D
Polyphen
0.73
P;.;.;P
Vest4
0.53
MVP
0.86
MPC
0.26
ClinPred
0.093
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.19
gMVP
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80356892; hg19: chr17-41244982; COSMIC: COSV100525443; COSMIC: COSV100525443; API