chr17-43092965-A-G

Position:

chr17-43092965-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

Clinical Significance

Benign reviewed by expert panel U:1B:29

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]

BRCA1 links:

BRCA1 (HGNC:):

BRCA1 links:

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/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.2566T>C	p.Tyr856His	missense_variant	10/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.2566T>C	p.Tyr856His	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152230

Hom.:

Cov.:

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.:

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.:

Cov.:

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:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

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.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00152

AC:

184

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:29

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:6

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	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 25, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jul 04, 2014	- -

not specified

Benign:7

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
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	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 18, 2019	- -
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. -

Hereditary cancer-predisposing syndrome

Benign:4

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. -
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	- -

not provided

Benign:3

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 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial cancer of breast

Benign:2

Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Likely benign, no assertion criteria provided	curation	Center for Precision Medicine, Meizhou People's Hospital	-	- -

Hereditary breast ovarian cancer syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

- -

BRCA1-related cancer predisposition

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Breast neoplasm

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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

- -

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) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, 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, â€šÃ„Ãºby a clinical laboratory(ies)â€šÃ„Ã¹), the BIC database (18X with unknown clinical importance, pending classification), and UMD (6X with a â€šÃ„Ãºneutralâ€šÃ„Ã¹ 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

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;T;T

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.5

M;M;.;.

PrimateAI

Uncertain

0.59

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over