rs80356892

chr17-43092965-A-Gchr17-43092965-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (5 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:28
• Conservation: PhyloP100: 3.23

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AD,AR gene

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: 92 AN: 152230 Hom.: 0 Cov.: 32

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

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

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

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:1 Benign:28

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:7

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 25, 2011	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -
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	literature only	Counsyl	Jul 04, 2014	- -

not specified Benign:7

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	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 18, 2019	- -
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	curation	Sema4, Sema4	Dec 11, 2020	- -
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	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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	BRCA1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -

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	Invitae	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

- -

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) “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;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N
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

Other links and lift over

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