chr17-43057077-C-T

Position:

chr17-43057077-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP6_Very_Strong

The NM_007294.4(BRCA1):c.5252G>A(p.Arg1751Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:16O:1

Conservation

PhyloP100: 3.17

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

BP6

Variant 17-43057077-C-T is Benign according to our data. Variant chr17-43057077-C-T is described in ClinVar as [Benign]. Clinvar id is 55481.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43057077-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5252G>A	p.Arg1751Gln	missense_variant	19/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.5252G>A	p.Arg1751Gln	missense_variant	19/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251492

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000672

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:16Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:4Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, 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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 14, 2016	- -
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 = 0.000206 -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: BRCA1 c.5252G>A (p.Arg1751Gln) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 5 splice prediction tools predict that this variant does not affect normal splicing, which was confirmed by an allelic-imbalance assay (Caux-Moncoutier_2009). The variant allele was found at a frequency of 3.6e-05 in 251492 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.1e-05 vs 1.00e-03), allowing no conclusion about variant significance. c.5252G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality (Stoppa-Lyonnet_1997, Gad_2002, deJuan_2009). In one large association study, the variant was found to be not associated with risk of breast cancer in the Caucasian population (Shimelis_2017). Multifactorial probability models report a neutral outcome (Easton_2007, Lindor_2012). At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA2 c.8346G>A, p.Trp2788X*), providing supporting evidence for a benign role. In addition, multiple functional assays suggest the variant of interest to have normal transcriptional activity, growth and localization activities as well as homology directed repair (example, Lee_2010, Rowling_2010, Williams_2003, and Thouvenot_2016, Lodovichi_2016, Woods_2016, Findlay_2018). Eight clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2017	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:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 08, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2021	- -
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. -

Breast and/or ovarian cancer

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 26, 2023	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BRCA1: BS3:Moderate -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2023	- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Arg1751Gln variant was identified in 6 of 96558 proband chromosomes (frequency: 0.000062) from individuals with breast cancer (Shimelis_2017_28283652, Gad_2002_ 12360411). The variant was found to not be associated with breast cancer in a large case-control study (Shimelis_2017_28283652). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8346G>A, p.Trp2788X), providing supporting evidence for a benign role (Integrated Genetics ClinVar submission, SCV000699228.2). The variant was identified in dbSNP (ID: rs80357442), ClinVar (Benign, 3 stars, reviewed by expert panel. Classified as benign by ENIGMA in 2015, Counsyl in 2016, Mendelics in 2019, Ambry in 2014, Women's College in 2014. Classified as likely benign by Quest Diagnostics in 2018, GeneDx in 2017, Invitae in 2019, Integrated Genetics in 2018, Color in 2016, CHEO in 2017. VUS by Mount Sinai, BIC, CSER), Cosmic (Identified in tissue from carcinoma of the breast), LOVD 3.0 (VUS, unclassified, benign), ARUP Laboratories (1 - Not pathogenic or of no clinical significance) databases. The variant was identified in control databases in 10 of 282888 chromosomes at a frequency of 0.00003535 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 2 of 35440 chromosomes (freq: 0.000056), European (non-Finnish) in 7 of 129194 chromosomes (freq: 0.000054), African in 1 of 24966 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. This variant is located in the Brca1 C-terminal (BRCT) domain; a domain that is involved in double-strand break repair. Multiple functional studies suggest the variant is neutral, though one suggested it may result in susceptibility to proteolysis (Petitalot_2019_30257991, Lee_2010_ 20516115, Rowling_2010_20378548, Williams_2004_ 15172985, Thouvenot_2016_ 27802165, Lodovichi_2016_27484786, Mirkovic_2004_ 15172985). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

.;T;.;.;T;T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

2.0

.;M;.;.;.;.;.;.

MutationTaster

Benign

0.99

D;D;D;D;D;D;D;D;D;D;D;D;N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.9

D;N;.;D;.;.;N;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.016

D;D;.;D;.;.;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D;D

Polyphen

0.95, 1.0

.;P;.;.;.;D;.;.

Vest4

0.95

MVP

0.84

MPC

0.098

ClinPred

0.22

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.74

gMVP

0.69

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