17-43093009-C-T

Position:

chr17-43093009-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):c.2522G>A(p.Arg841Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R841W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: 0.227

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 -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43093010-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.021051377).

BP6

Variant 17-43093009-C-T is Benign according to our data. Variant chr17-43093009-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 54591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43093009-C-T is described in Lovd as [Likely_benign]. Variant chr17-43093009-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.2522G>A	p.Arg841Gln	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.2522G>A	p.Arg841Gln	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152158

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251058

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461514

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000481

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	BRCA1: BP1, BP4, BS3:Moderate -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	This variant is associated with the following publications: (PMID: 20104584, 23867111, 15385441, 18273839, 21520273, 11400546, 8968716, 16267036, 23893897, 19370767, 33087888) -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 30, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 04, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 26, 2019

Variant summary: BRCA1 c.2522G>A (p.Arg841Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 283280 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.2e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.2522G>A, has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Barker_1996, Borg_2010, Judkins_2005, Schoumacher_2001, Brianese_2018, Zuntini_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2126insA, [p.Phe709TyrfsX3; BRCA2 c.7069_7070delCT , p.Leu2357ValfsX2; BRCA1 c.5152+2T>G), providing supporting evidence for a benign role. Additionally, one publication reports the variant present in a breast cancer patient, but absent in her affected mother, while both patients had a different pathogenic BRCA1 mutation, suggesting lack of segregation of the variant with disease (Zuntini_2018). Two publications have conducted functional studies: one used minigene splicing assays (Anczukow_2008) and one used functional complementation assays in cultured mouse embryonic stem cells (Bouwman_2013), both of which showed no significant effect on function caused by the variant. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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.Arg841Gln variant was identified in 2 of 4282 proband chromosomes (frequency: 0.0004) from individuals or families with hereditary breast and ovarian cancer (Borg 2010, Schoumacher 2001). The variant was also identified in dbSNP (ID: rs80357337) â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, Exome Aggregation Consortium (ExAC) database, HGMD 3X, the ClinVar database 5X with conflicting classifications (classified as benign (SCRP and Ambry Genetics), likely benign (GeneDx), and uncertain significance (BIC - 6X); UMD reported the variant (10X as a likely neutral variant) and the Exome Aggregation Consortium (ExAC) database in 5 of 66708 (European (Non-Finnish)) alleles (frequency: 0.00007495), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. In UMD the variant was identified with two co-occurring pathogenic variants, a BRCA1 variant p.Phe709TyrfsX3, and a BRCA2 variant p.Leu2357ValfsX2 increasing the likelihood that the p.Arg841Gln variant does not have clinical significance. The p.Arg841 residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in orangutans, macaques, mice, dogs, cows, frogs and sea urchins, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In addition, functional studies based on the physiologic expression of the full length BRCA1 cDNA in mice (Bouwman 2013) and in silico studies (Capanu 2011) showed the variant to be neutral. One in 5 splicing software suggested that this variant may create an alternative 3' splice site (human splicing finder), but this information is not very predictive of pathogenicity. Lastly, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, the clinical significance of this variant could not be determined with absolute certainty although we would lean towards a more benign role for this variant. This variant meets our laboratory's criteria to be classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.13

CADD

Benign

1.1

DANN

Benign

0.72

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.63

T;T;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-2.5

N;N;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

3.4

N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.33

MutPred

0.63

Loss of phosphorylation at S840 (P = 0.0969);Loss of phosphorylation at S840 (P = 0.0969);.;Loss of phosphorylation at S840 (P = 0.0969);

MVP

0.27

MPC

0.093

ClinPred

0.038

GERP RS

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.020

gMVP

0.026

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